ES2821962T3 - Sodium channel blocker - Google Patents

Abstract

A compound represented by Chemical Formula 1 below, or a pharmaceutically acceptable salt thereof: ** (See formula) ** in Chemical Formula 1, R1 is hydrogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, halogen or cyano, R2 and R3 are each independently hydrogen or halogen, R4 is thiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl or thiadiazolyl, wherein R4 is unsubstituted or substituted with C1-4 alkyl or halogen, R5 is -CH2CH2-N (R7) (R8) or -CH2CH2CH2-N (R7) (R8), R6 is hydrogen or C1-4 alkyl; or R5 and R6 together form C3-5 alkylene, (C2-4 alkylene) -N (R9) - (C2-4 alkylene) or (C2-4 alkylene) -O- (C2-4 alkylene), where each C3-5 alkylene, or C2-4 alkylene is independently unsubstituted or substituted with one or two R10, R7, R8 and R9 are each independently hydrogen, or C1-4 alkyl, R10 is C1-4 alkyl, C1-4 alkoxy, halogen, amino, NH (C1-4 alkyl), N (C1-4 alkyl) 2, NHCO (C1-4 alkyl) or pyrrolidinyl, X1 is CR 'or N, where R' is hydrogen or halogen, X2 is CH or N, and X3 is NR ", where R" is hydrogen or C1-4 alkyl.

Description

DESCRIPTION

Sodium channel blocker

[Technical field]

The present invention relates to a compound having sodium ion channel blocking activity, a process for preparing and using the same.

[Background of the technique]

Voltage-gated sodium (Nav) channels are found in all excitable cells, including nerve and muscle cells of the central and peripheral nervous systems. Sodium channels are essential for the initiation and propagation of electrical signals in the nervous system. Therefore, proper sodium channel function is essential for normal nerve function. Ultimately, abnormal Nav channels play an important role in various diseases such as epilepsy, arrhythmia, myotonia, ataxia, multiple sclerosis, irritable bowel syndrome, urinary incontinence, visceral pain, depression and pains. Currently, ten types of Nav channels have been found in humans (Nav 1.1—1.9, Nax). Among these, the four channels Nav1.3, Nav1.7, Nav1.8, and Nav 1.9 are known to have a close connection with pain signaling and are therefore recognized as an important target of analgesic drugs.

So far, a total of 10 types of Nav channels have been found, as summarized in Table 1 below. Among the 10 types, 9 types from Nav 1.1 to Nav1.9 form channels, among which NG 1.3, Nav 1.6, Nav 1.7, Nav 1.8 and Nav 1.9 are expressed in DRG.

[Table 1]*

In particular, Nav1.7 is known to be preferentially expressed in dorsal root ganglia (DRG) and sympathetic ganglia. In DRG sensory ganglia, the Nav1.7 channel is expressed in A-fiber or C-fiber neurons, but they are frequently distributed in small neurons that have a deep connection to pain. In particular, 85% of DRGs are present in cells defined as nociceptors. This fact indicates that Nav1.7 has a close connection with pain.

The fact that the Nav1.7 channel has a close connection to pain is well demonstrated in results, not only from animal studies, but also in human disease studies. Results from animal studies indicate that, when inflammation occurs, transcription of the Nav1.7 gene is significantly increased and protein expression also increases. This increase in transcription is believed to be attributable to an increase in NGF. Increased expression of Nav1.7 is believed to be the direct cause of increased excitability of sensory cells. In particular, when the Nav1.7 channel gene is deleted or reduced, inflammatory pain is greatly reduced. However, animal studies do not indicate that deletion or reduction of the Nav1.7 channel gene reduces neuropathic pain. However, there is much evidence that Nav1.7 is involved in neuropathic pain in humans.

Survey results for lineages experiencing severe or no pain give many answers to studies of pain. In particular, these results directly indicate the importance of Nav1.7 in causing pain. There are two types of inherited diseases that cause severe pain. In the case of erythromelalgia or erythemalgia among these diseases, severe pain is sometimes felt for a few hours when the body is slightly warm or exercising. In some cases, the skin becomes red and the hands, feet, or face swell. Genetic research results indicated that SCN9A (named after the human gene for Nav1.7) it is present at chromosomal sites associated with disease. So far, nine Nav1.7 mutations have been found. These mutations lower the activation threshold or result in slow deactivation of the channel. Thus, these mutations can easily generate an action potential even after depolarization of some neurons (see Dib-Hajj, S D. et al., Trends in Neurosci., 30, 555-563: (2007)).

In the case of paroxysmal extreme pain disorder (PEPD), which is another inherited disease, pain is felt throughout life and occurs when the bowels are evacuated or the anal region is stimulated. In addition to the pain, the legs become red. As is known in the art, in PEPD, eight mutations occur in Nav1.7. These mutations occur primarily at sites that cause inactivation. The Nav channel has an inactivation ball in the linker between domains III and IV, and a peptide receptor region in the linker between the S5 and S6 segments of domains III and IV. Interestingly, all the mutations that cause PEPD occur in these two regions. These seem to cause a problem with the inactivation of Nav1.7. As expected, these mutations cause a problem in inactivation of Nav1.7, resulting in slow inactivation of the channel (see Fertleman, C. R. et al., Neuron, 52, 767-774 (2006)). Therefore, the amount of electrical current entering the channel increases.

Another inherited disease is congenital indifference to pain (CIP). This disease is the result of the Nav1.7 channel mutation and exists in the lineage of Pakistanis and Chinese. People with this disease do not feel pain (see Cox, J. J. et al., Nature, 444, 894-898 (2006)). The CIP causes the loss of function of the Nav1.7 channel. In particular, a mutation in this channel inhibits the expression of this channel. Therefore, this channel is not expressed (see Cox, J. J. et al., Nature, 444, 894-898 (2006)). Interestingly, the gene deactivation of Nav1.7 does not influence other sensations. However, it influences the olfactory sensation. This fact directly indicates that Nav1.7 does not overlap with other channels in pain transmission and its function is not compensated by other Nav channels.

As described above for the above diseases, when a mutation in the Nav1.7 channel causes a gain of function, severe pain is felt and when it causes a loss of function, the pain is relieved. This is a good clinical example that directly shows that the Nav1.7 channel is the main cause of pain. Therefore, it has been considered that an antagonist that inhibits this channel will have a natural analgesic effect.

However, if the Nav1.7 channel antagonist inhibits a plurality of Nav channels, including the Nav1.7 channel, it may show adverse effects with various CNS disturbances, such as blurred vision, dizziness, vomiting, and depression. In particular, if it inhibits the Nav1.5 channel, it can lead to cardiac arrhythmias and heart failure, which are life-threatening. For these reasons, selective inhibition of Nav1.7 channels is very important.

Pain has three broad classifications: acute pain, inflammatory pain, and neuropathic pain. Acute pain plays an important protective role by keeping organisms safe from stimuli that can cause tissue damage. Therefore, it is generally temporary and intense. On the other hand, inflammatory pain may last longer and its intensity increases even more. Inflammatory pain is mediated by various substances that are released during inflammation, including substance P, histamine, acids, prostaglandin, bradykinin, CGRP, cytokines, ATP, and other substances. The third pain is neuropathic and involves a nerve injury or nerve injury caused by a viral infection. This causes the reconstitution of circuits with neuronal proteins to cause pathological "sensitization", which can result in chronic pain that lasts for several years. This type of pain does not provide an adaptability advantage and is difficult to treat with current therapy.

In particular, neuropathic pain and intractable pain are major unresolved medical problems. Several hundred million patients suffer from severe pain that is not well inhibited by current therapeutic methods. Drugs currently used for pain management include NSAIDS, COX-2 inhibitors, opioids, tricyclic antidepressants, and anticonvulsants. Neuropathic pain is particularly difficult to treat, because it does not respond well to opioids until a high dose is reached. Currently, gabapentin is the most widely used as a therapeutic agent against neuropathic pain, but it is effective for 60 % of patients and it is not very effective. This drug is generally safe, but it is problematic in terms of sedative action in high doses.

Consequently, global pharmaceutical companies, including Merck, AstraZeneca and the like, have conducted studies to discover new regulators of the Nav1.7 channel and use them for the treatment of acute pain, acute chronic pain, inflammatory pain, and neuropathic pain. (see US2010-0197655; US2012-0010183; WO2013-086229; WO2013-177224; US2012-0238579; WO2007-145922).

In view of the above, as a result of the study of new compounds, the present inventors have found that a compound having a different chemical structure from the sodium channel blockers described so far not only has excellent sodium channel blocking effects. sodium, to thus complete the present invention. The compounds belonging to the present invention mainly have sodium channel inhibitory activity by themselves, but do not exclude the possibility of exhibiting a pharmacological action as an effective agent by a special body environment or by products of the metabolic process, after their absorption in the body.

[Detailed description of the invention]

[Technical Problem]

It is an object of the present invention to provide a compound having a blocking effect against sodium ion channels, particularly Nav 1.7, a process for its preparation and use.

[Technical solution]

To achieve the above objectives, the present invention provides a compound represented by Chemical Formula 1 below, or a pharmaceutically acceptable salt thereof:

in Chemical Formula 1,

R ¹ is hydrogen, C ^1-4 alkyl, C ^1-4 alkoxy, C ^1-4 haloalkyl, C ^1-4 haloalkoxy, halogen or cyano,

R ² and R ³ are each independently hydrogen or halogen,

R ⁴ is thiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl or thiadiazolyl,

wherein R4 is unsubstituted or substituted with C1-4 alkyl or halogen,

R ⁵ is -CH ² CH ² -N (R ⁷ ) (R8) or -CH ² CH ² CH ² -N (R ⁷ ) (R8), R6 is hydrogen or C ^1-4 alkyl; or R ⁵ and R6 together form C ^3-5 alkylene, (C ^2-4 alkylene) -N (R9) - (C2-4 alkylene) or (C ^2-4 alkylene) -O - (C ^2-4 alkylene) ,

wherein each of the C ^3-5 alkylene, or C ^2-4 alkylene is independently unsubstituted or substituted with one or two R ¹⁰ ,

R ⁷ , R8 and R ⁹ are each independently hydrogen, or C ^1-4 alkyl,

R ¹⁰ is C ^1-4 alkyl, C ^1-4 alkoxy, halogen, amino, NH (C1-4 alkyl), N (C1-4 alkyl) ² , NHCO (C1-4 alkyl) or pyrrolidinyl, X ¹ is CR 'or N, where R' is hydrogen or halogen,

X ² is CH or N, and

X ³ is NR ", where R" is hydrogen or C ^1-4 alkyl.

Preferably, the compound represented by Chemical Formula 1 is represented by Chemical Formula 1 'below:

where,

Ri is hydrogen, C ^1-4 alkyl, C ^1-4 alkoxy, C ^1-4 haloalkyl, C ^1-4 haloalkoxy, halogen or cyano,

R ² and R ³ are each independently hydrogen or halogen,

R ⁴ is thiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl or thiadiazolyl,

wherein R4 is unsubstituted or substituted with C1-4 alkyl or halogen,

R ¹¹ is hydrogen or C ^1-4 alkyl,

R ¹² is hydrogen, C ^1-4 alkyl, C ^1-4 alkoxy, halogen, amino, NH (C ^1-4 alkyl), N (C1-4 alkyl) ² , NHCO (C1-4 alkyl) or pyrrolidinyl,

X ¹ is CR 'or N, where R' is hydrogen or halogen,

X ² is CH or N, and

X ³ is NR ", where R" is hydrogen or C ^1-4 alkyl,

X ⁴ is a bond, NH, N (C1-4 alkyl) or O (oxygen), and

n is an integer from 1 to 4.

Preferably R ¹ is hydrogen, methyl, methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine or cyano. Preferably R ² and R ³ are each independently hydrogen, fluorine or chlorine.

Preferably R ⁵ and R6 together form C ^3-5 alkylene, (C ^2-4 alkylene) -N (R ⁹ HC ^2-4 alkylene) or (C ^2-4 alkylene) -O- (C ^2-4 alkylene) , wherein each of the C ^3-5 alkylene or C ^2-4 alkylene is independently unsubstituted or substituted with methyl, methoxy, fluoro, amino, NHCH ³ , N (CH ³ ) ² , N (CH ² CH ³ ) ² , NHCOCH ³ or pyrrolidinyl.

Preferably, R ⁵ , ^{R6 and R 5} and R6 together with the nitrogen to which they are attached, form any of those selected from the group consisting of:

where R ¹⁰ is as defined above.

Preferably, R ⁵ is -CH ² CH ² -NH -CH ³ , -CH ² CH ² CH ² -NH -CH ³ or -CH ² CH ² -N (CH ³ ) ² , and R6 is hydrogen or methyl. Preferably, X ¹ is CH, CF, or N, X ² is CH, or N, as long as both X ¹ and X ² are not N.

Preferably X ³ is NH.

Representative examples of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof are as follows:

1) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide, 2) 5-chloro-4 - ((4-chloro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide, 3) (R ) -5-chloro-4 - ((4-chloro-2- (2-methylpiperazin-1-yl) phenyl) amino) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide, 4) (R) -5-chloro-4 - ((4-chloro-2- (3- (methylamno) p¡per¡d¡n-1-¡l) phen¡l) am¡no ) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide,

5) (R) -N- (1- (5-chloro-2 - ((2-chloro-5-fluoro-4- (N- (thiazol-4-¡l) sulfamo¡l) phenyl ) am¡no) phen¡l) p¡rrol¡d¡n-3-¡l) acetamide, 6) 5-chloro-4 - ((4-chloro-2- (3- (d¡et¡ lam¡no) p¡rrol¡d¡n-1-¡l) phen¡l) am¡no) -2-fluoro-N- (th¡azol-4-¡l) benzenesulfonamide, 7) 4- ((2 - ([1,3'-b¡p¡rrol¡d¡n] -1'-¡l) -4-chlorophenyl) am¡no) -5-chloro-2-fluoro-N- (thiazol-4-¡l) benzenesulfonamide, 8) 5-chloro-2-fluoro-4 - ((4-methyl-2- (3- (methylamine) p¡rrol¡ d¡n-1-¡l) phen¡l) am¡no) -N- (thiazol-4-¡l) benzenesulfonamide, 9) (S) -5-chloro-4 - ((4- chloro-2- (3-methylp¡peraz¡n-1-¡l) phen¡l) am¡no) -2-fluoro-N- (th¡azol-4-¡l) benzenesulfonamide, 10 ) 4 - ((4-fluoro-2- (3- (methylamine) p¡rrol¡d¡n-1-¡l) phenl) amino) -N- (thiazol- 4-¡l) benzenesulfonamida,

11) 3-chloro-4 - ((4-fluoro-2- (3- (methylamno) p¡rrol¡d¡n-1-¡l) phenl) amino) -N- (thiazol-4-¡l) benzenesulfonamide, 12) 3,5-d¡fluoro-4 - ((4-fluoro-2- (3- (methylamine) p¡rrol¡d¡ n-1 - ¡l) phen¡l) am¡no) -N- (th¡azol-4-¡l) benzenesulfonamide, 13) 2-fluoro-4 - ((4-fluoro-2- (3 - (methylamine) p¡rrol¡d¡n-1-¡l) phen¡l) am¡no) -N- (th¡azol-4-¡l) benzenesulfonamide, 14) 4- ((2- (3- (methyllamine) p¡rrol¡d¡n-1-¡l) -4- (tr¡fluoromethox¡) phen¡l) am¡no) -N- (t¡ azole-4-¡l) benzenesulfonam¡da, 15) 3,5-d¡fluoro-4 - ((2- (3- (meth¡lam¡no) p¡rrol¡d¡n-1-¡l) -4- (trifluoromethoxy) phenyl) amine) -N- (thiazol-4-¡l) benzenesulfonamide,

16) 2-fluoro-4 - ((2- (3- (methyllamine) p¡rrol¡d¡n-1-¡l) -4- (tr¡fluoromethox¡) phen¡l) am¡ no) -N- (thiazol-4-¡l) benzenesulfonamide,

17) 5-chloro-2-fluoro-4 - ((2- (3- (methylamno) p¡rrol¡d¡n-1-¡l) -4- (tr¡fluoromethox¡) fen¡ l) amino) -N- (thiazol-4-¡l) benzenesulfonamide,

18) 5-chloro-4 - ((5-chloro-3- (3- (meth¡lam¡no) p¡rrol¡d¡n-1-¡l) p¡r¡d¡n-2-¡ l) amine) -2-fluoro-N- (thiazol-4-l) benzenesulfonamide,

19) 5-chloro-4 - ((6-chloro-2- (3- (meth¡lam¡no) p¡rrol¡d¡n-1-¡l) p¡r¡d¡n-3-¡ l) amine) -2-fluoro-N- (thiazol-4-l) benzenesulfonamide,

20) 5-chloro-2-fluoro-4 - ((2- (3- (methylamno) p¡rrol¡d¡n-1-¡l) -4- (tr¡fluorometh¡l) fen ¡L) amine) -N- (thiazol-4-¡l) benzenesulfonamide,

21) 5-chloro-4 - ((4- (d¡fluoromethoxy¡) -2- (3- (meth¡lam¡no) p¡rrol¡d¡n-1-¡l) phen¡l) am¡ no) -2-fluoro-N- (thiazol-4-¡l) benzenesulfonamide,

22) (R) -4 - ((4-fluoro-2- (3- (methylamine) p¡per¡d¡n-1-¡l) phenl) am¡no) -N- (thiazol-4-¡l) benzenesulfonamide,

23) (R) -2-fluoro-4 - ((4-fluoro-2- (3- (methylamine) p¡per¡d¡n-1-¡l) phen¡l) am¡no ) -N- (thiazol-4-¡l) benzenesulfonamide, 24) (R) -3-chloro-4 - ((4-fluoro-2- (3- (methylamine) p¡ per¡d¡n-1-¡l) phen¡l) am¡no) -N- (th¡azol-4-¡l) benzenesulfonamide, 25) (R) -3,5-d¡fluoro- 4 - ((4-fluoro-2- (3- (methylamine) p¡per¡d¡n-1-¡l) phen¡l) am¡no) -N- (th¡azol-4 -¡L) benzenesulfonam¡da, 26) (R) -5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylam¡no) p¡per¡n- 1-¡l) phenl) amino) -N- (thiazol-4-¡l) benzenesulfonamide,

27) (R) -4 - ((4-fluoro-2- (3- (methylamine) p¡rrol¡d¡n-1-¡l) phenl) amine) -N- (thiazol-4-¡l) benzenesulfonamide,

28) (R) -2-fluoro-4 - ((4-fluoro-2- (3- (methylamno) p¡rrol¡d¡n-1-¡l) phen¡l) am¡no ) -N- (thiazol-4-¡l) benzenesulfonamide, 29) (R) -3-chloro-4 - ((4-fluoro-2- (3- (methylamine) p¡ rrol¡d¡n-1-¡l) phen¡l) am¡no) -N- (th¡azol-4-¡l) benzenesulfonamide, 30) (R) -3,5-d¡fluoro- 4 - ((4-fluoro-2- (3- (methylamine) p¡rrol¡d¡n-1-¡l) phenl) amino) -N- (th¡azol-4 -¡L) benzenesulfonam¡da, 31) (R) -5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylam¡no) p¡rrol¡d¡n- 1-¡l) phenl) amino) -N- (thiazol-4-¡l) benzenesulfonamide,

32) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamno) p¡rrol¡d¡n-1-¡l) phen¡l) am¡no ) -N- (thiazol-4-¡l) benzenesulfonamide, 33) 4 - ((2- (3-am¡nopyrrol¡d¡n-1-¡l) -4-fluorophenyl) am¡no) -2-fluoro-N- (th¡azol-4 -¡L) benzenesulfonamide, 34) 4 - ((2- (3-am¡nopyrrol¡d¡n-1-¡l) -4-fluorophenyl) am¡no) -3-chloro-N- (thiazol-4-¡l) benzenesulfonamide,

35) 4 - ((2- (3-am¡nopyrrol¡d¡n-1-¡l) -4-fluorophenyl) am¡no) -5-chloro-2-fluoro-N- (t ¡Azole-4-¡l) benzenesulfonam¡da, 36) 4 - ((2- (3- (meth¡lam¡no) p¡rrol¡d¡n-1-¡l) phen¡l) am¡no ) -N- (thiazol-4-¡l) benzenesulfonamide,

37) 2-fluoro-4 - ((2- (3- (methyllamine) p¡rrol¡d¡n-1-¡l) -4- (tr¡fluoromethyl) phen¡l) am ¡No) -N- (thiazol-4-¡l) benzenesulfonamida, 38) 3-chloro-4 - ((2- (3- (methylamno) p¡rrol¡d¡n- 1-¡l) -4- (tr¡fluoromethyl) phen¡l) am¡no) -N- (th¡azol-4-¡l) benzenesulfonamide, 39) 4 - ((4- (d ¡Fluoromethoxy!) -2- (3- (methylamine) p¡rrol¡d¡n-1-¡l) phen¡l) am¡no) -2-fluoro-N- (th¡azole- 4-¡l) benzenesulfonamida,

40) 3-chloro-4 - ((4- (d¡fluoromethox¡) -2- (3- (meth¡lam¡no) p¡rrol¡d¡n-1-¡l) phen¡l) am¡ no) -N- (thiazol-4-¡l) benzenesulfonamida, 41) (R) -4 - ((4-fluoro-2- (3-fluorop¡rrol¡d¡n-1-¡l ) phenyl) amino) -N- (thiazol-4-¡l) benzenesulfonamide,

42) (R) -2-fluoro-4 - ((4-fluoro-2- (3-fluorop¡rrol¡d¡n-1-¡l) phen¡l) am¡no) -N- (t¡ azole-4-¡l) benzenesulfonamide,

43) (R) -3-chloro-4 - ((4-fluoro-2- (3-fluorop¡rrol¡d¡n-1-¡l) phen¡l) am¡no) -N- (t¡ azole-4-¡l) benzenesulfonamide,

44) (R) -3,5-d¡fluoro-4 - ((4-fluoro-2- (3-fluorop¡rrol¡d¡n-1-¡l) phen¡l) am¡no) -N - (thiazol-4-¡l) benzenesulfonamide, 45) (R) -5-chloro-2-fluoro-4 - ((4-fluoro-2- (3-fluorop¡rrol¡d¡n- 1-¡l) phen¡l) am¡no) -N- (th¡azol-4-¡l) benzenesulfonamida, 46) 2-fluoro-4 - ((3-fluoro-2- (3- ( methylamine) pyrolidin-1-¡l) phenyl) amino) -N- (thiazol-4-¡l) benzenesulfonamide, 47) 3-chloro- 4 - ((3-fluoro-2- (3- (methylamine) p¡rrol¡d¡n-1-¡l) phenl) amino) -N- (thiazol-4 -¡L) benzenesulfonam¡da, 48) 5-chloro-2-fluoro-4 - ((3-fluoro-2- (3- (methylam¡no) p¡rrol¡d¡n-1-¡l ) phenyl) amino) -N- (thiazol-4-¡l) benzenesulfonamida, 49) 2-fluoro-4 - ((2- (3- (methylamine) p¡ rrol¡d¡n-1-¡l) phen¡l) am¡no) -N- (th¡azol-4-¡l) benzenesulfonamide,

50) 3-chloro-4 - ((2- (3- (methylamine) pırrol¡d¡n-1-¡l) phenl) amine) -N- (thiazole -4-¡l) benzenesulfonamida,

51) 3,5-d¡fluoro-4 - ((2- (3- (methylamine) p¡rrol¡d¡n-1-¡l) phenl) amino) -N- (thiazol-4-¡l) benzenesulfonamide,

52) 5-chloro-2-fluoro-4 - ((2- (3- (methylamine) p¡rrol¡d¡n-1-¡l) phenl) amino) -N- (thiazol-4-¡l) benzenesulfonamide, 53) 2-fluoro-4 - ((4-methoxy-2- (3- (methylamine) p¡rrol¡d¡n-1 -¡L) phen¡l) amino) -N- (thiazol-4-¡l) benzenesulfonamide, 54) 3-chloro-4 - ((4-methoxy-2- (3- ( methylamine) pyrolidin-1-¡l) phen¡l) amino) -N- (thiazol-4-¡l) benzenesulfonamide, 55) 5-chloro- 2-fluoro-4 - ((4-methoxy-2- (3- (methylamine) p¡rrol¡d¡n-1-¡l) phenl) amine) -N- ( thiazol-4-¡l) benzenesulfonamida,

56) (R) -4 - ((4-methoxy-2- (3- (methlamine) pnperdn-1-l) phenl) amine) -N - (thiazol-4-¡l) benzenesulfonamida,

57) (R) -2-fluoro-4 - ((4-methoxy-2- (3- (methylamine) p¡per¡d¡n-1-¡l) phen¡l) am¡ no) -N- (thiazol-4-¡l) benzenesulfonamide, 58) (R) -3-chloro-4 - ((4-methoxy-2- (3- (methylamine) p¡per¡d¡n-1-¡l) phen¡l) am¡no) -N- (th¡azol-4-¡l) benzenesulfonam¡da, 59) (R) -3,5-d¡ fluoro-4 - ((4-methox¡-2- (3- (methylamine) p¡per¡d¡n-1-¡l) phen¡l) am¡no) -N- (t¡ azole-4-¡l) benzenesulfonamide, 60) (R) -5-chloro-2-fluoro-4 - ((4-methoxy-2- (3- (methylamine) piper¡ d¡n-1-¡l) phen¡l) am¡no) -N- (th¡azol-4-¡l) benzenesulfonamide,

61) 3-chloro-4 - ((4-fluoro-2- (4-methylp¡peraz¡n-1-¡l) phen¡l) am¡no) -N- (th¡azol-4- L) benzenesulfonamide,

62) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (4-methylp¡peraz¡n-1-¡l) phen¡l) am¡no) -N- (t¡ azole-4-¡l) benzenesulfonam¡da, 63) (S) -5-chloro-4 - ((2- (3- (d¡melam¡no) p¡rrol¡d¡n-1-¡ l) -4-fluorophenyl) amino) -2-fluoro-N- (thiazol-4-¡l) benzenesulfonamide,

64) (S) -5-chloro-4 - ((2- (3- (d¡met¡lam¡no) p¡rrol¡d¡n-1-¡l) -4- (tr¡fluorometh¡l ) phenl) amino) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide,

65) 5-chloro-2-fluoro-4 - ((2- (4-methylp¡peraz¡n-1-¡l) -4- (tr¡fluorome¡l) phen¡l) am¡no) -N- (thiazol-4-¡l) benzenesulfonamide,

66) 5-chloro-4 - ((4- (d¡fluoromethox¡) -2- (4-methylp¡peraz¡n-1-¡l) phen¡l) am¡no) -2-fluoro- N- (thiazol-4-¡l) benzenesulfonamide,

67) 5-chloro-2-fluoro-4 - ((2- (4-methylp¡peraz¡n-1-¡l) -4- (tr¡fluoromethox¡) phen¡l) am¡no) - N- (thiazol-4-¡l) benzenesulfonamide,

68) (S) -3-chloro-4 - ((2- (3- (d¡met¡lam¡no) p¡rrol¡d¡n-1-¡l) -4- (tr¡fluorometh¡l ) phenyl) amino) -N- (thiazol-4-¡l) benzenesulfonamide,

69) (S) -2-fluoro-4 - ((4-fluoro-2- (3- (methylamno) p¡rrol¡d¡n-1-¡l) phen¡l) am¡no ) -N- (thiazol-4-¡l) benzenesulfonamide, 70) (S) -5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylam¡ no) p¡rrol¡d¡n-1-¡l) phen¡l) am¡no) -N- (th¡azol-4-¡l) benzenesulfonam¡da,

71) (S) -5-chloro-4 - ((2- (3- (d¡meth¡lam¡no) p¡rrol¡d¡n-1-¡l) -4-methoxyphen¡l) amino) -2-fluoro-N- (thiazol-4-¡l) benzenesulfonamida,

72) (S) -5-chloro-4 - ((4- (d¡fluoromethox¡) -2- (3- (d¡met¡lam¡no) p¡rrol¡d¡n-1-¡l) phenyl) amino) -2-fluoro-N- (thiazol-4-¡l) benzenesulfonamide,

73) (R) -5-chloro-4 - ((2- (3- (d¡meth¡lam¡no) p¡rrol¡d¡n-1-¡l) -4-fluorophenyl) am¡ no) -2-fluoro-N- (thiazol-4-¡l) benzenesulfonamide,

74) (R) -5-chloro-4 - ((2- (3- (d¡met¡lam¡no) p¡rrol¡d¡n-1-¡l) -4- (tr¡fluorometh¡l ) phenyl) amine) -2-fluoro-N- (thiazol-4-¡l) benzenesulfonamide,

75) (R) -5-chloro-4 - ((4- (d¡fluoromethox¡) -2- (3- (d¡met¡lam¡no) p¡rrol¡d¡n-1-¡l) phenyl) amino) -2-fluoro-N- (thiazol-4-¡l) benzenesulfonamide,

76) 4 - ((2- (1,4-d¡azepan-1-¡l) -4-fluorophenyl) am¡no) -5-chloro-2-fluoro-N- (th¡azol-4 -¡L) benzenesulfonam¡da, 77) 5-chloro-4 - ((4-kano-2- (3- (methylamine) p¡rrol¡d¡n-1-¡l) fen ¡L) amine) -2-fluoro-N- (thiazol-4-¡l) benzenesulfonamide, 78) (R) -N- (1- (2 - ((2-chloro-5- fluoro-4- (N- (thiazol-4-¡l) sulfamo¡l) phen¡l) am¡no) -5- (tr¡fluorome¡l) phen¡l) p¡rrol¡d¡n -3-l) acetamide,

79) (R) -N- (1- (2 - ((2-chloro-4- (N- (thiazol-4-¡l) sulfamo¡l) phenyl) amine) -5- (tr¡fluorometh¡l) phen¡l) p¡rrol¡d¡n-3-¡l) acetamide, 80) (S) -3-chloro-4 - ((2- (3- (met¡ lam¡no) p¡rrol¡d¡n-1-¡l) -4- (tr¡fluoromethyl) phen¡l) am¡no) -N- (th¡azol-4-¡l) benzenesulfonam¡ gives,

81) (S) -5-chloro-2-fluoro-4 - ((2- (3- (methylamine) p¡rrol¡d¡n-1-¡l) -4- (tr¡fluoromet ¡L) phenl) amino) -N- (thiazol-4-¡l) benzenesulfonamide,

82) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamno) acetyl) amino) - N- (thiazol-4-¡l) benzenesulfonamide, 83) 4 - ((2- (3-am¡noacet¡d¡n-1-¡l) -4-fluorophen¡l) am¡no ) -5-chloro-2-fluoro-N- (thiazol-4-¡l) benzenesulfonamide, 84) 5-chloro-4 - ((2- (3- (dimethylamine) acetyn-1-¡l) -4-fluorophenyl) am¡no) -2-fluoro-N- (th¡azol-4-¡l) benzenesulfonamide,

85) N- (1- (2 - ((2-chloro-5-fluoro-4- (N- (thiazol-4-¡l) sulfamo¡l) phenyl) amine) -5- fluorophenyl) acetyl-3-¡l) acetamide, 86) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3-methoxyp¡rrol¡d¡ n-1-¡l) phen¡l) am¡no) -N- (th¡azol-4-¡l) benzenesulfonamide, 87) 5-chloro-2-fluoro-4 - ((2- (3 -methox¡pyrrol¡d¡n-1-¡l) -4- (tr¡fluorometal) phen¡l) am¡no) -N- (th¡azol-4-¡l) benzenesulfonam¡da ,

88) (R) -N- (1- (2 - ((2-chloro-5-fluoro-4- (N- (thiazol-4-¡l) sulfamo¡l) phen¡l) am¡no ) -5-fluorophen¡l) p¡rrol¡d¡n-3-¡l) acetamide, 89) 3-chloro-4 - ((4-fluoro-2- (3-methox¡pyrrol¡d¡n-1-¡l) phen¡l) am¡no) -N- (th¡azol- 4-¡l) benzenesulfonamide, 90) 3-chloro-4 - ((2- (3-methoxy¡pyrrol¡d¡n-1-¡l) -4- (tr¡fluoromethyl) phen¡l ) amino) -N- (thiazol-4-¡l) benzenesulfonamida, 91) (R) -N- (1- (2 - ((2-chloro-4- (N- (t¡ azole-4-¡l) sulfamo¡l) phen¡l) am¡no) -5-fluorophen¡l) p¡rrol¡d¡n-3-¡l) acetamide,

92) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamine) ethyl) amine) phenyl) amine) -N- (thiazol-4-¡l) benzenesulfonamide,

93) 3-chloro-4 - ((2 - ((2- (dimethylamine) ethyl) (methyl) amine) -4-fluorophenyl) amine) - N- (thiazol-4-¡l) benzenesulfonamide, 94) 5-chloro-4 - ((2 - ((2- (d¡methylam¡no) eth¡l) (methyl) amino) -4-fluorophenyl) amino) -2-fluoro-N- (thiazol-4-¡l) benzenesulfonamide,

95) 5-chloro-2-fluoro-4 - ((2- (methyl (2- (methylamine) ethyl) amine) -4- (trifluoromethyl) phen l) amino) -N- (thiazol-4-¡l) benzenesulfonamide,

96) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamine) ethyl) amine) phenyl) amine) -N- (5-fluorop¡r¡m¡d¡n-2-¡l) benzenesulfonam¡da,

97) 5-chloro-2-fluoro-N- (5-fluorop¡r¡m¡d¡n-2-¡l) -4 - ((2- (methyl (2- (meth¡lam¡no ) ethyl) amine) -4- (trifluoromethyl) phenl) amine) benzenesulfonamide,

98) 5-chloro-4 - ((4- (d¡fluoromethox¡) -2- (methyl (2- (methylamine) ethyl) amine) phenyl) amine ) -2-fluoro-N- (thiazol-4-¡l) benzenesulfonamide,

99) 5-chloro-4 - ((4-kano-2- (methyl (2- (methylamine) ethyl) amine) phenl) amine) -2 -fluoro-N- (thiazol-4-¡l) benzenesulfonamide,

100) 5-chloro-4 - ((4-kano-2- (methyl (2- (methylamine) ethyl) amine) phenl) amine) -2 -fluoro-N- (5-fluorop¡r¡m¡d¡n-2-¡l) benzenesulfonamida,

101) 5-chloro-4 - ((4- (d¡fluoromethox¡) -2- (methyl (2- (methylamine) ethyl) amine) phenyl) amine ) -2-fluoro-N- (5-fluorop¡r¡nn¡d¡n-2-¡l) benzenesulfonamide,

102) 5-chloro-2-fluoro-N- (5-fluorop¡r¡m¡d¡n-2-¡l) -4 - ((2- (methyl (2- (meth¡lam¡no ) ethyl) amine) phenyl) amine) benzenesulfonamide,

103) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamine) ethyl) amine) phenyl) amine) -N- (5-fluorop¡r¡d¡n-2-¡l) benzenesulfonam¡da,

104) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamine) ethyl) amine) phenyl) amine) -N- (p¡r¡d¡n-2-¡l) benzenesulfonam¡da,

105) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamine) ethyl) amine) phenyl) amine) -N- (thiazol-2-¡l) benzenesulfonamide,

106) 5-chloro-4 - ((4-kano-2- (methyl (2- (methylamine) ethyl) amine) phenl) amine) -2 -fluoro-N- (5-fluorop¡r¡d¡n-2-¡l) benzenesulfonam¡da,

107) 5-chloro-4 - ((4-kano-2- (methyl (2- (methylamine) ethyl) amine) phenl) amine) -2 -fluoro-N- (p¡r¡d¡n-2-¡l) benzenesulfonamida,

108) 5-chloro-4 - ((4-kano-2- (methyl (2- (methylamine) ethyl) amine) phenl) amine) -2 -fluoro-N- (thiazol-2-¡l) benzenesulfonamide,

109) 5-chloro-2-fluoro-N- (5-fluorop¡r¡d¡n-2-¡l) -4 - ((2- (methyl (2- (methylamine) et ¡L) am¡no) -4- (tr¡fluorometal) phen¡l) am¡no) benzenesulfonamide,

110) 5-chloro-2-fluoro-4 - ((2- (methyl (2- (methylamine) ethyl) amine) -4- (trifluoromethyl) phen l) am¡no) -N- (p¡r¡d¡n-2-¡l) benzenesulfonam¡da,

111) 5-chloro-2-fluoro-4 - ((2- (methyl (2- (methylamine) ethyl) amine) -4- (trifluoromethyl) phen l) amino) -N- (thiazol-2-¡l) benzenesulfonamide,

112) 5-0! oro-2-fluoro-N- (5-fluorop¡ r¡d¡n-2-¡l) -4 - ((2- (methyl (2- (meth¡lam¡no) eth¡l ) amine) phenl) amine) benzenesulfonamide,

113) 5-chloro-2-fluoro-4 - ((2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -N- (pyridin-2-yl) benzenesulfonamide, 114) 5-chloro- 2-fluoro-4 - ((2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -N- (thiazol-2-yl) benzenesulfonamide, 115) 5-chloro-4 - ((4- (difluoromethoxy) -2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -2-fluoro-N- (5-fluoropyridin-2-yl) benzenesulfonamide,

116) 5-chloro-4 - ((4- (difluoromethoxy) -2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -2-fluoro-N- (thiazol-2-yl) benzenesulfonamide,

117) 5-chloro-4 - ((4- (difluoromethoxy) -2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -2-fluoro-N- (pyridin-2-yl) benzenesulfonamide,

118) 5-chloro-2-fluoro-N- (5-fluoropyrid in-2-yl) -4 - ((4-m ethoxy-2- (m ethyl (2- (methylamino) ethyl) amino) phenyl) amino ) benzenesulfonamide,

119) 5-chloro-2-fluoro-4 - ((4-methoxy-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -N- (thiazol-2-yl) benzenesulfonamide,

120) 5-chloro-2-fluoro-4 - ((4-methoxy-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide,

121) 5-chloro-2-fluoro-4 - ((2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide, 122) 5-chloro- 2-fluoro-N- (5-fluoropyrim idin-2-yl) -4 - ((4-methoxy-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) benzenesulfonamide,

123) 5-chloro-4 - ((4-chloro-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide,

124) 5-chloro-4 - ((4-chloro-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -2-fluoro-N- (5-fluoropyrimidin-2-yl) benzenesulfonamide,

125) 5-chloro-4 - ((4-chloro-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -2-fluoro-N- (5-fluoropyridin-2-yl) benzenesulfonamide,

126) 5-chloro-4 - ((4-chloro-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -2-fluoro-N- (thiazol-2-yl) benzenesulfonamide,

127) 5-chloro-N - (5-chlorothiazol-2-yl) -2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) benzenesulfonamide ,

128) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -N- (5-fluorothiazol-2-yl) benzenesulfonamide,

129) 5-chloro-N- (5-chlorothiazol-2-yl) -2-fluoro-4 - ((2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) benzenesulfonamide, 130) 5- chloro-N- (5-chlorothiazol-2-yl) -2-fluoro-4 - ((4-m ethoxy-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) benzenesulfonamide,

131) 5-chloro-2-fluoro-N- (5-fluorothiazol-2-yl) -4 - ((2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) benzenesulfonamide,

132) 5-chloro-2-fluoro-N- (5-fluorothiazol-2-yl) -4 - ((4-m ethoxy-2- (m ethyl (2- (methylamino) ethyl) amino) phenyl) amino) benzenesulfonamide,

133) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -N- (5-methylisoxazol-3-yl) benzenesulfonamide,

134) 5-chloro-2-fluoro-4 - ((2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -N- (5-methylisoxazol-3-yl) benzenesulfonamide,

135) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -N- (5-methyl-1H-pyrazole-3- yl) benzenesulfonamide,

136) 5-chloro-2-fluoro-4 - ((2- (methyl (2- (methylamine) ethyl) amine) phenyl) amine) -N- ( 5-methyl-1H-prazol-3-yl) benzenesulfonamide,

137) 5-chloro-4 - ((2 - ((2- (dimethylamine) ethyl) (methyl) amine) -4-fluorophenyl) amine) - 2-fluoro-N- (5-fluorop¡r¡d¡n-2-¡l) benzenesulfonam¡da,

138) 5-chloro-4 - ((2 - ((2- (dimethyl) ethyl) (methyl) amine) -4-fluorophenyl) amine) - 2-fluoro-N- (thiazol-2-¡l) benzenesulfonamide,

139) 5-chloro-N- (5-chlorot¡azol-2-¡l) -4 - ((2 - ((2- (dimet¡lam¡no) eth¡l) (methyl) am No) -4-fluorophene (l) amine) -2-fluorobenzenesulfonamide,

140) 5-chloro-N- (5-chlorot¡azol-2-¡l) -4 - ((2 - ((2- (dimet¡lam¡no) eth¡l) (methyl) am No) phenl) amine) -2-fluorobenzenesulfonamide,

141) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamine) ethyl) amine) phenyl) amine) -N- (5-methyllazol-2-¡l) benzenesulfonamide,

142) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamine) ethyl) amine) phenyl) amine) -N- (oxazol-2-¡l) benzenesulfonamide,

143) N- (5- (tert-butyl) ¡soxazol-3-¡l) -5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (met ¡Lam¡no) eth¡l) am¡no) phen¡l) am¡no) benzenesulfonamide,

144) N- (5- (tert-butyl) ¡soxazol-3-¡l) -5-chloro-2-fluoro-4 - ((2- (methyl (2- (methylamine ) ethyl) amine) phenyl) amine) benzenesulfonamide,

145) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamno) p¡rrol¡d¡n-1-¡l) phen¡l) am¡no ) -N- (1,2,4-thiazol-5-¡l) benzenesulfonamide,

146) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamno) p¡rrol¡d¡n-1-¡l) phenl) am¡no ) -N- (1-methyl-1 Hprazole-3-¡l) benzenesulfonamide,

147) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamno) p¡rrol¡d¡n-1-¡l) phen¡l) am¡no ) -N- (p¡r¡m¡d¡n-4-¡l) benzenesulfonam¡da,

148) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamno) p¡rrol¡d¡n-1-¡l) phen¡l) am¡no ) -N- (5-fluorop¡r¡m¡d¡n-2-¡l) benzenesulfonam¡da,

149) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamno) p¡rrol¡d¡n-1-¡l) phen¡l) am¡no ) -N- (p¡raz¡n-2-¡l) benzenesulfonam¡da,

150) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamno) p¡rrol¡d¡n-1-¡l) phen¡l) am¡no ) -N- (5-meth¡l¡soxazol-3-¡l) benzenesulfonamida,

151) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamno) p¡rrol¡d¡n-1-¡l) phenl) am¡no ) -N- (p¡r¡m¡d¡n-5-¡l) benzenesulfonam¡da,

152) 5-chloro-2-fluoro-4 - ((4-fluoro-2 - ((2- (methylamine) ethyl) amine) phenyl) amine) -N- (thiazol-4-¡l) benzenesulfonamida, 153) 5-chloro-4 - ((2 - ((2- (d¡methylam¡no) eth¡l) am¡no) -4- fluorophenyl) amino) -2-fluoro-N- (thiazol-4-¡l) benzenesulfonamide, and

154) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (3- (methylamine) propyl) amine) phenyl) amine) -N- (thiazol-4-l) benzenesulfonamide.

Furthermore, the compounds of the present invention may exist in the form of salts, especially pharmaceutically acceptable salts. As salts, the salts commonly used in the art, such as the acid addition salts formed by pharmaceutically acceptable free acids, can be used. . The term "pharmaceutically acceptable salt", as used herein, refers to any organic or organic addition salt of the compound represented by the Chemical Formula. ca 1, whose concentration is relatively non-toxic and non-offensive for the patient and works effectively and whose secondary effects do not degrade the effectiveness of benefits. Ose of the above compound.

As the free acid, an organic acid and an organic acid can be used. Examples of norganic acids include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid. co ys¡m¡lares. Examples of Organic acids include methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, Propionic Acid, Citric Acid, Lactic Acid, Glycolic Acid, Gluconic Acid, Galacturonic Acid, Glutamic Acid, Glutaric Acid, Glucuronic Acid, Aspartic Acid, Ascorbic Acid, Carbonic Acid, Vanillic Acid , hydroiodic acid and the like, but not limited to these.

Furthermore, a pharmaceutically acceptable metal salt can be obtained by a conventional method by using a base. For example, a compound represented by Chemical Formula 1 is dissolved in an excessive amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, the insoluble salt is filtered, and the filtrate is evaporated and dried to obtain a pharmaceutically acceptable metal salt. . At this time, it is particularly preferred to prepare a sodium salt, a potassium salt or a calcium salt such as the metal salt.

A pharmaceutically unacceptable salt or solvate of the compound of Chemical Formula 1 can be used as an intermediate when preparing the compound of Chemical Formula 1, or the pharmaceutically acceptable salt or solvate thereof.

Furthermore, the compound of Chemical Formula 1 according to the present invention includes not only the pharmaceutically acceptable salts thereof, but also solvates such as hydrates which can be prepared therefrom, and includes all possible stereoisomers, but not limited to these. The solvate and stereoisomer of the compound of Chemical Formula 1 can be prepared from the compound of Chemical Formula 1 using common methods known in the art.

Furthermore, the compound of Chemical Formula 1 according to the present invention can be prepared in crystalline or non-crystalline form, and when the compound of Chemical Formula 1 is prepared in crystalline form, it can optionally be hydrated or solvated. In the present invention, the compound of Chemical Formula 1 can not only include a stoichiometric hydrate, but can also include a compound that contains various amounts of water. The solvate of the compound of Chemical Formula 1 according to the present invention includes both stoichiometric and non-stoichiometric solvates.

Furthermore, as an example, the present invention can produce the compound represented by Chemical Formula 1 through Reaction Scheme 1 below.

in Reaction Scheme 1, X ¹ to X ⁴ , R ¹ to R6, and n are as previously defined in Chemical Formula 1.

According to steps i, ii and iii, the respective compounds represented by Chemical Formulas 1-3 and 1-6 can be prepared as intermediates. Step i is preferably reacted at 50 to 60 ° C in the presence of potassium carbonate, and the solvent is preferably dimethylformamide. Stage ii is preferably carried out at 50 to 60 ° C in the presence of sodium hyposulfite and, as solvent, a mixture of ethanol and water (1: 1) is preferably used. Step iii is preferably carried out at -78 ° C in the presence of lithium hexamethyldisilylamide and the solvent is preferably tetrahydrofuran.

The intermediate product represented by Chemical Formula 1-7 can be prepared according to step iv. The above step is a reaction step of the compound represented by Chemical Formula 1-3 with the compound represented by Chemical Formula 1-6. The reaction is preferably carried out at 120 ° C in the presence of palladium diacetate, bis (diphenylphosphino) binaphthyl and cesium carbonate, and the solvent is preferably dioxane.

The compound represented by Chemical Formula 1 can be obtained according to step v. The reaction is preferably carried out at 60 to 80 ° C in the presence of hydrochloric acid, and the solvent is preferably methanol. Furthermore, depending on the type of substituent from R ¹ to R6, if it is necessary to protect in the reaction of steps i to iv, steps i to iv can be carried out in a state of protection with a protecting group, which can be eliminate then in stage v.

Furthermore, the present invention provides a pharmaceutical composition for preventing or treating diseases, which is effective for sodium channel blocking activity, which comprises the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt, hydrate or solvate. thereof as an active ingredient.

In this case, the disease includes acute pain, chronic pain, neuropathic pain, postoperative pain, migraine, arthralgia, neuropathy, nerve damage, diabetic neuropathy, neuropathic disease, epilepsy, arrhythmia, myotonia, ataxia, multiple sclerosis, irritable bowel syndrome, urinary incontinence, visceral pain, depression, erythralgia, PEPD (paroxysmal extreme pain disorder) or the like.

As used herein, the term "prevention" refers to any act to delay or inhibit the onset, spread or recurrence of the aforementioned diseases by administering the composition of the present invention and "treatment" refers to any act to improve or change the symptoms of the above diseases by administering the composition of the present invention.

The pharmaceutical composition according to the present invention can be formulated in types for oral or parenteral administrations, in accordance with standard pharmaceutical practice. These formulations may contain additives such as pharmaceutically acceptable carriers, adjuvants, or diluents, in addition to the active ingredient.

Suitable carriers include, for example, physiological saline, polyethylene glycol, ethanol, vegetable oil, isopropyl myristate, and the like. Diluents include, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine and the like, but are not limited to these. Furthermore, the compounds of the present invention can be dissolved in oils, propylene glycol or other solvents commonly used in the preparation of injectable solutions. In addition, the compounds of the present invention can be formulated into ointments or creams for topical application.

A preferred dose of the compound of the present invention can be varied according to the condition and weight of a patient, the severity of a disease, the type of drug, and the route and duration of administration, but can be suitably selected by those skilled in the art The technique. To achieve the convenient effects, the compound of the present invention can be administered daily at a dose of 0.0001 to 100 mg / kg (body weight) and preferably 0.001 to 100 mg / kg (body weight). Administration can be done once a day or in divided doses each day, orally or parenterally.

Depending on the method of administration, the pharmaceutical composition may contain the compound of the present invention in an amount of 0.001 to 99 % by weight, preferably 0.01 to 60 % by weight.

The pharmaceutical composition according to the present invention can be administered to mammals such as a rat, a mouse, a domestic animal, a human, through various routes. Administration can be carried out by all possible methods, for example, oral, rectal, intravenous, intramuscular, subcutaneous, intraendometrial, intracerebroventricular injection.

[Advantageous Effects]

The compound represented by Chemical Formula 1 according to the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof, can be usefully used for the prevention or treatment of diseases related to sodium channel blockers. .

[Detailed description of the modalities]

Below, the present invention will be described in detail through examples. However, the following examples are provided for illustrative purposes only and the scope of the present invention should not be construed to be limited to these examples.

Example 1: Preparation of 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide hydrochloride

Step 1) Preparation of tert-butyl (1- (2-amino-5-fluorophenyl) pyrrolidin-3-yl) (methyl) carbamate

2,4-Difluoro-1-nitrobenzene (2.0 g, 12.6 mmol) and tert-butylmethyl (pyrrolidin-3-yl) carbamate (2.5 g, 1.0 eq.) Were dissolved in DMF (20 mL), and then K ² CO ³ (2.6 g, 1.5 eq.) was added thereto. While maintaining the internal temperature at 60 to 70 ° C, the reaction mixture was stirred for 2 hours. When the reaction solution turned dark yellow, the completion of the reaction was confirmed by TLC. After cooling to room temperature, ethyl acetate (EA) / H ²⁰ was added and stirred, and then the layers were separated. MgSO4 was added to the separated organic layer, which was stirred, dried, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was dissolved in EtOH (10 mL) and distilled water (10 mL), to which Na2S2O4 (13.0 g, 6 eq.) Was added. While maintaining the internal temperature at 60 to 70 ° C, the reaction mixture was stirred for 2 hours. When the yellow color of the reaction solution faded and became almost colorless, the completion of the reaction was confirmed by TLC. After cooling to room temperature, distilled water (50 mL) was added and extracted twice with EA (100 mL). MgSO4 was added to the organic layer, which was stirred, dried, and then filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was separated by column chromatography (n-hexane / EA = 3/1) to obtain the title compound (2.0 g, 51.1%).

1H NMR (MeOD): 6.73 (m, 1H), 6.57 (t, 1H), 3.23 (m, 1H), 3.10 (m, 2H), 2.94 (m, 1H) , 2.91 (s, 3H), 2.25 (m, 1H), 1.99 (m, 1H)

Step 2) Preparation of tert-butyl thiazol-4-yl carbamate

Thiazole-4-carboxylic acid (5.0 g, 38.8 mmol) was dissolved in t-BuOH (100 mL), and then TEA (8.1 mL, 1.5 eq.) and DPPA (7.1 mL, 1 , 5 eq.) Were added thereto. While maintaining the internal temperature at 90 to 100 ° C, the reaction mixture was stirred for 3 days, and then the completion of the reaction was confirmed by TLC. The product was concentrated under reduced pressure, distilled water (50 mL) was added, and extracted twice with EA (100 mL). MgSO4 was added to the organic layer, which was stirred, dried, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was added to a small amount of EA and suspended. The resulting solid was filtered to obtain a white title compound (4.0 g, 51.5%).

1H NMR (MeOD): 8.73 (s, 1H), 7.24 (s, 1H), 1.52 (s, 9H)

Step 3) Preparation of tert-butyl ((4-bromo-5-chloro-2-fluorophenyl) sulfonyl) (thiazol-4-yl) carbamate

Tert-butyl thiazol-4-yl carbamate (4.0 g, 20.0 mmol) prepared in Step 2) was added to a reaction vessel and the interior of the vessel was replaced with nitrogen gas. After dissolving in THF (32 mL), the solution was cooled to -78 ° C using dry ice-acetone. After cooling, LiHMDS (22.4 mL, 1.5 eq.) Was added slowly and the reaction mixture was stirred for 30 minutes. 4-Bromo-5-chloro-2-fluorobenzenesulfonyl chloride (6.0 g, 1.0 eq.) Was dissolved in THF (10 mL) and then slowly added to the reaction solution. The reaction mixture was stirred overnight and completion of the reaction was confirmed by TLC. Distilled water (50 mL) was added and extracted twice with EA (100 mL). MgSO4 was added to the organic layer, which was stirred, dried, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was crystallized from THF / n-hexane to obtain the title compound (4.4 g, 59.0%).

1H NMR (MeOD): 9.00 (s, 1H), 8.22 (d, 1H), 7.90 (d, 1H), 7.78 (s, 1H), 1.35 (s, 9H)

Step 4) Preparation of tert-butyl (1 - (2 - ((4 - (N - (tert-butoxycarbonyl) -N- (thiazol-4-yl) sulfamoyl) -2-chloro-5-fluorophenyl) amino) - 5-fluorophenyl) pyrrolidin-3-yl) (methyl) carbamate

Tert-butyl (1- (2-amino-5-fluorophenyl) pyrrolidin-3-yl) (methyl) carbamate (0.5 g, 1.1 mmol) prepared in Step 1) and tert-butyl ((4-bromo- 5-chloro-2-fluorophenyl) sulfonyl) (thiazol-4-yl) carbamate (0.9 g, 1.2 eq.) Prepared in Step 3) were dissolved in 1,4-dioxane (10 mL). Pd (OAc) 2 (0.03 g, 0.1 eq.), Rac-BINAP (0.19 g, 0.2 eq.) And Cs2CO3 (1.5 g, 3.0 eq.) Were added to the reaction solution. After reacting at 120 ° C for 30 minutes using a midrowave initiator, the completion of the reaction was confirmed by TLC. Distilled water (50 mL) was added and extracted twice with EA (100 mL). MgSO4 was added to the organic layer, which was stirred, filtered, and then dried. The filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (EA / n-hexane = 1/1). This procedure was repeated twice to obtain the title compound (2.0 g, 88.2%).

1H NMR (MeOD): 8.95 (s, 1H), 7.94 (d, 1H), 7.65 (s, 1H), 7.14 (t, 1H), 6.70 (d, 1H), 6 , 64 (t, 1H), 6.07 (d, 1H), 3.40 (m, 1H), 3.28 (m, 2H), 3.16 (m, 1H), 2.64 (s, 3H), 2.06 (m, 1H), 1.89 (m, 1H), 1.41 (s, 9H), 1.36 (s, 9H)

Step 5) Preparation of 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide hydrochloride

A tert-butyl (1 - (2 - ((4- (N - (tert-butoxycarbonyl) -N- (thiazol-4-yl) sulfamoyl) -2-chloro-5-fluorophenyl) amino) -5-fluorophenyl) Pyrrolidin-3-yl) (methyl) carbamate (2.0 g, 2.9 mmol) prepared in Step 4) 1.25 M HCl in MeOH (15 mL) was added. After stirring the mixture overnight while warming to 40 to 50 ° C, completion of the reaction was confirmed by TLC. The product was concentrated, methylene chloride (15 mL) was added to the obtained residue, stirred for 1 hour, and the solid product was filtered to give the title compound (0.9 g, 58.8%).

1H NMR (MeOD): 8.73 (s, 1H), 7.75 (d, 1H), 7.12 (t, 1H), 7.00 (s, 1H), 6.69 (d, 1H) , 6.67 (t, 1H), 6.05 (d, 1H), 3.73 (m, 1H), 3.54 (m, 1H), 3.45 (m, 1H), 3.38 ( m, 1H), 3.26 (m, 1H), 2.63 (s, 3H), 2.31 (m, 1H), 1.96 (m, 1H)

Hereafter, the compounds of Examples 2 to 9 were prepared in the same manner as described in Example 1, except for the reagents that correspond to the structures of the compounds that are produced while in use.

Example 2: Preparation of 5-chloro-4 - ((4-chloro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide hydrochloride

1H NMR (500 MHz, MeOD): 8.79 (s, 1H), 7.74 (d, 1H), 7.09 (d, 1H), 7.02 (s, 1H), 6.98 (s , 1H), 6.92 (d, 1H), 6.13 (d, 1H), 3.76 (m, 1H), 3.53 (m, 3H), 2.64 (s, 3H), 2 , 31 (m, 1H), 2.01 (m, 1H), 1.27 (m, 1H)

Example 3: Preparation of (R) -5-chloro-4 - ((4-chloro-2- (2-m ethylpiperazin-1-yl) phenyl) amino) -2-fluoro-N- (thiazol-4- yl) benzenesulfonamide hydrochloride

1H NMR (500 MHz, MeOD): 8.73 (d, 1H), 7.84 (d, 1H), 7.38 (d, 1H), 7.30 (d, 1H), 7.28 (d , 1H), 7.04 (d, 1H), 6.99 (d, 1H), 3.40 (m, 3H), 3.15 (m, 2H), 3.07 (m, 1H), 2 , 86 (m, 1H), 0.93 (m, 3H)

Example 4: Preparation of (R) -5-chloro-4 - ((4-chloro-2- (3- (methylamino) piperidin-1-yl) phenyl) amino) -2-fluoro-N- (thiazol-4 -il) benzenesulfonamide hydrochloride

1H NMR (500 MHz, MeOD): 8.75 (d, 1H), 7.80 (d, 1H), 7.28 (d, 1H), 7.20 (d, 1H), 7.17 (m , 1H), 7.03 (d, 1H), 6.58 (d, 1H), 3.44 (m, 1H), 3.02 (m, 1H), 2.94 (m, 1H), 2 , 78 (m, 1H), 2.67 (s, 3H), 2.08 (m, 1H), 1.79 (m, 1H), 1.50 (m, 1H), 1.41 (m, 1H), 0.87 (m, 1H)

Example 5: Preparation of (R) -N - (1- (5-chloro-2 - ((2-c-chloro-5-fluoro-4- (N - (thiazol-4-yl) sulfamoyl) phenyl) amino) phenyl) pyrrolidin-3-yl) acetamide hydrochloride

1H NMR (500 MHz, MeOD): 8.78 (m, 1H), 7.76 (d, 1H), 7.17 (d, 1H), 7.08 (m, 1H), 7.02 (s , 1H), 6.92 (m, 1H), 6.15 (t, 1H), 4.26 (m, 1H), 3.55 (m, 1H), 3.35 (m, 1H), 3 , 25 (m, 1H), 2.27 (m, 1H), 1.93 (m, 1H), 1.90 (s, 3H)

Example 6: Preparation of 5-chloro-4 - ((4-chloro-2- (3- (diethylamino) pyrrolidin-1-yl) phenyl) amino) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide hydrochloride

1H NMR (500 MHz, MeOD): 8.78 (d, 1H), 7.77 (d, 1H), 7.12 (d, 1H), 7.03 (m, 1H), 6.99 (dd , 1H), 6.03 (d, 1H), 4.08 (m, 1H), 3.52 (m, 3H), 3.17 (m, 4H), 3.05 (m, 1H), 2 , 39 (m, 1H), 2.01 (m, 1H), 1.26 (m, 6H)

Example 7: Preparation of 4 - ((2 - ([1,3'-bipyrrolidin] -1'-yl) -4-chlorophenyl) amino) -5-chloro-2-fluoro-N- (thiazol-4- yl) benzenesulfonamide hydrochloride

1H NMR (500 MHz, MeOD): 8.76 (d, 1H), 7.77 (d, 1H), 7.11 (d, 1H), 7.02 (m, 2H), 6.97 (m , 1H), 6.07 (d, 1H), 3.91 (m, 1H), 3.50 (m, 5H), 3.22 (m, 1H), 3.05 (m, 2H), 2 , 36 (m, 1H), 1.97 (m, 5H)

Example 8: Preparation of 5-chloro-2-fluoro-4 - ((4-methyl-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide hydrochloride

1H NMR (500 MHz, MeOD): 8.76 (d, 1H), 7.74 (d, 1H), 7.02 (m, 2H), 6.91 (s, 1H), 6.85 (d , 1H), 6.16 (d, 1H), 3.78 (m, 1H), 3.45 (m, 3H), 3.23 (m, 1H), 2.65 (s, 3H), 2 , 35 (s, 3H), 2.34 (m, 1H), 2.01 (m, 1H)

Example 9: Preparation of (S) -5-chloro-4 - ((4-chloro-2- (3-m ethylpiperazin-1-yl) phenyl) amino) -2-fluoro-N- (thiazol-4- yl) benzenesulfonamide hydrochloride

1H NMR (500 MHz, MeOD): 8.73 (d, 1H), 7.79 (d, 1H), 7.29 (d, 1H), 7.20 (m, 2H), 7.03 (d , 1H), 6.54 (d, 1H), 3.88 (m, 1H), 3.44 (s, 3H), 3.04 (m, 1H), 2.97 (m, 1H), 2 , 80 (m, 1H), 1.27 (m, 3H)

Example 10: Preparation of 4 - ((4-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

Intermediate tert-butyl (1- (2 - ((4- (N- (tert-butoxycarbonyl) -N- (thiazolo-4-N) sulfamoN) phenyl) amino) -5-fluorophenyl) pyrrolidin-3-yl) (Methyl) carbamate was prepared in the same manner as described in steps 1 to 4 of Example 1, except that 4-bromobenzenesulfonyl chloride was used in place of 4-bromo-5-chloro-2-fluorobenzenesulfonyl chloride in Step 3 of Example 1.

To the intermediate obtained, 1.25 M HCl in MeOH (15 mL) was added. After stirring the mixture overnight while warming to 40 to 50 ° C, completion of the reaction was confirmed by TLC. The product was concentrated, and the obtained residue was separated and purified by PLC to obtain 0.05 g of the target compound (yield: 48%).

1H NMR (500 MHz, MeOD): 8.68 (s, 1H), 7.57 (d, 2H), 7.07 (t, 1H), 6.92 (s, 1H), 6.66-6 , 54 (m, 4H), 3.42-3.30 (m, 4H), 3.14-3.13 (m, 1H), 2.42 (s, 3H), 2.18-2.16 (m, 1H), 1.84-1.40 (m, 1H)

Hereafter, the compounds of Examples 11 to 91 were prepared in the same manner as described in Example 10, except for the reagents that correspond to the structures of the compounds that are produced while in use.

Example 11: Preparation of 3-chloro-4 - ((4-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.69 (s, 1H), 7.74 (s, 1H), 7.47 (d, 1H), 7.05 (t, 1H), 6.93 (s , 1H), 6.63 (d, 1H), 6.54 (t, 1H), 6.33 (d, 1H), 3.40-3.37 (m, 2H), 3.17-3, 11 (m, 3H), 2.31 (s, 3H), 2.08-2.00 (m, 1H), 1.72-1.68 (m, 1H)

Example 12: Preparation of 3,5-difluoro-4 - ((4-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.73 (s, 1H), 7.43 (d, 2H), 7.04 (s, 1H), 6.63 (t, 1H), 6.75 (d , 1H), 6.60 (t, 1H), 3.66-3.63 (m, 1H), 3.49-3.35 (m, 3H), 3.08-3.04 (m, 1H ), 2.63 (s, 3H), 2.31-2.28 (m, 1H), 1.96-1.93 (m, 1H)

Example 13: Preparation of 2-fluoro-4 - ((4-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.68 (s, 1H), 7.56 (t, 1H), 7.03 (t, 1H), 6.84 (s, 1H), 6.63 (d , 1H), 6.55 (t, 1H), 6.40 (d, 1H), 6.23 (d, 1H), 3.35-3.30 (m, 3H), 3.18-3, 16 (m, 2H), 2.36 (s, 3H), 2.11-2.05 (m, 1H), 1.78-1.75 (m, 1H)

Example 14: Preparation of 4 - ((2- (3- (methylamino) pyrrolidin-1-yl) -4- (trifluoromethoxy) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.68 (s, 1H), 7.60 (d, 2H), 7.16 (d, 1H), 6.92 (s, 1H), 6.77-6 , 68 (m, 4H), 3.38-3.61 (m, 1H), 3.35-3.33 (m, 2H), 3.28-3.27 (m 1H), 3.09- 3.06 (m, 1H), 2.36 (s, 3H), 2.36-2.35 (m, 1H), 1.85-1.83 (m, 1H)

Example 15: Preparation of 3,5-difluoro-4 - ((2- (3- (methylamine) pyrrolidin-1-yl) -4- (trifluoromethoxy) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.62 (s, 1H), 7.41 (d, 2H), 6.87 (s, 1H), 6.76-6.75 (m, 1H), 6 , 69-6.67 (m, 2H), 3.59 (s, 1H), 3.49-3.47 (m, 2H), 3.25-3.23 (m, 1H), 2.99 -2.98 (m, 1H), 2.59 (s, 3H), 2.29-2.27 (m, 1H), 1.99-1.97 (m, 1H)

Example 16: Preparation of 2-fluoro-4 - ((2- (3- (methylamino) pyrrolidin-1-yl) -4- (trifluoromethoxy) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.68 (s, 1H), 7.58 (t, 1H), 7.16 (d, 1H), 6.84 (s, 1H), 6.84-6 , 83 (m, 2H), 6.49 (d, 1H), 6.35 (d, 1H), 3.38-3.34 (m, 3H), 3.23-3.21 (m, 1H ), 3.12-3.10 (m, 1H), 2.41 (s, 3H), 2.18-2.16 (m, 1H), 1.85-1.83 (m, 1H) Example 17: Preparation of 5-chloro-2-fluoro-4 - ((2- (3- (methylamine) pyrrolidin-1-yl) -4- (trifluoromethoxy) phenyl) amino) -N- (thiazol-4- yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.68 (s, 1H), 7.74 (d, 1H), 7.15 (d, 1H), 6.85 (s, 1H), 6.75-6 , 74 (m, 2H), 6.04 (d, 1H), 3.45-3.38 (m, 3H), 3.19-3.17 (m, 2H), 2.40 (s, 3H ), 2.13-2.12 (m, 1H), 1.80-1.79 (m, 1H)

Example 18: Preparation of 5-chloro-4 - ((5-chloro-3- (3- (methylamino) pyrrolidin-1-yl) pyridin-2-yl) amino) -2-fluoro-N- (thiazol-4 -il) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.68 (d, 1H), 8.30 (d, 1H), 7.96 (d, 1H), 7.84 (d, 1H), 7.53 (d , 1H), 6.87 (d, 1H), 3.44 (m, 3H), 3.10 (m, 2H), 2.50 (s, 3H), 2.36 (m, 1H), 1 , 95 (m, 1H)

Example 19: Preparation of 5-chloro-4 - ((6-chloro-2- (3- (methylamino) pyrrolidin-1-yl) pyridin-3-yl) amino) -2-fluoro-N- (thiazol-4 -il) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.69 (s, 1H), 7.76 (s, 1H), 7.34 (s, 1H), 6.90 (m, 2H), 6.70 (s , 1H), 6.01 (d, 1H), 3.45 (m, 3H), 2.99 (m, 2H), 2.49 (s, 3H), 2.11 (m, 2H)

Example 20: Preparation of 5-chloro-2-fluoro-4 - ((2- (3- (methylamino) pyrrolidin-1-yl) -4- (trifluoromethyl) phenyl) amino) -N- (thiazol-4-yl ) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.67 (d, 1H), 7.78 (d, 1H), 7.26 (d, 1H), 7.16 (m, 2H), 6.81 (d , 1H), 6.21 (d, 1H), 3.39 (m, 3H), 3.17 (m, 2H), 2.43 (s, 3H), 2.13 (m, 1H), 1 , 94 (m, 1H)

Example 21: Preparation of 5-chloro-4 - ((4- (difluoromethoxy) -2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -2-fluoro-N- (thiazol-4-yl ) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.63 (d, 1H), 7.73 (d, 1H), 7.07 (d, 1H), 6.70 (t, 2H), 6.62 (t , 2H), 6.03 (d, 1H), 3.40 (m, 3H), 3.23 (m, 2H), 2.42 (s, 3H), 2.11 (m, 1H), 1 , 83 (m, 1H)

Example 22: Preparation of (R) -4 - ((4-fluoro-2- (3- (methylamino) piperidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.68 (s, 1H), 7.61 (d, 2H), 7.17 (t, 1H), 6.89 (s, 1H), 6.77-6 , 75 (m, 3H), 6.74-6.73 (m, 1H), 3.34-3.30 (m, 1H), 2.88-2.59 (m, 4H), 2.32 (s, 3H), 1.82-1.70 (m, 2H), 1.45-1.44 (m, 2H)

Example 23: Preparation of (R) -2-fluoro-4 - ((4-fluoro-2- (3- (methylamino) piperidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.68 (s, 1H), 7.61 (t, 1H), 7.20 (t, 1H), 6.87 (d, 1H), 6.85-6 , 81 (m, 2H), 6.78 (d, 1H), 6.67 (d, 1H), 3.34 (s, 1H), 2.92-2.79 (m, 4H), 2, 48 (s, 3H), 1.89-1.87 (m, 2H), 1.79-1.78 (m, 1H), 1.47-1.46 (m, 1H)

Example 24: Preparation of (R) -3-chloro-4 - ((4-fluoro-2- (3- (methylamino) piperidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.69 (s, 1H), 7.80 (s, 1H), 7.54 (s, 1H), 7.24-7.21 (m, 1H), 6 , 89-6.77 (m, 4H), 3.01-2.97 (m, 1H), 2.68-2.41 (m, 3H), 2.30 (s, 3H), 1.86 -1.84 (m, 1H), 1.68-1.66 (m, 1H), 1.40-1.35 (m, 2H)

Example 25: Preparation of (R) -3,5-difluoro-4 - ((4-fluoro-2- (3- (methylamino) piperidin-1-yl) phenyl) amino) -N- (thiazol-4-yl ) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.64 (s, 1H), 7.41 (d, 2H), 6.85 (d, 1H), 6.75-6.66 (m, 3H), 3 , 26-3.24 (m, 1H), 2.88-2.78 (m, 4H), 2.55 (s, 3H), 1.87-1.86 (m, 1H) 1.85- 1.83 (m, 1H), 1.74-1.72 (m, 1H), 1.37-1.35 (m, 1H)

Example 26: Preparation of (R) -5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamino) piperidin-1-yl) phenyl) amino) -N- (thiazol-4 -il) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.66 (s, 1H), 7.77 (d, 1H), 7.22 (t, 1H), 6.89-6.84 (m, 2H), 6 , 81 (s, 1H), 6.35 (d, 1H), 3.38-3.36 (m, 1H), 3.03-3.01 (m, 1H), 2.63-2.61 (m, 1H), 2.48-2.44 (m, 2H), 2.37 (s, 3H), 1.89-1.87 (m, 1H), 1.68-1.66 (m , 1H), 1.32-1.32 (m, 2H)

Example 27: Preparation of (R) -4 - ((4-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.68 (s, 1H), 7.56 (d, 2H), 7.04 (t, 1H), 6.92 (s, 1H), 6.63-6 , 53 (m, 4H), 3.24-3.21 (m, 3H), 3.14-3.10 (m, 2H), 2.31 (s, 3H), 2.11-2.08 (m, 1H), 1.73-1.70 (m, 1H)

Example 28: Preparation of (R) -2-fluoro-4 - ((4-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.68 (s, 1H), 7.57-7.53 (m, 1H), 7.05-7.03 (m, 1H), 6.83 (s, 1H), 6.62 (d, 1H), 6.55-6.53 (m, 1H), 6.40 (d, 1H), 6.23 (d, 1H), 3.34-3.30 (m, 2H), 3.28-3.27 (m, 1H), 3.18-3.15 (m, 2H), 2.36 (s, 3H), 2.13-2.10 (m , 1H), 1.76-1.74 (m, 1H)

Example 29: Preparation of (R) -3-chloro-4 - ((4-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.68 (s, 1H), 7.75 (s, 1H), 7.47-7.45 (m, 1H), 7.06-7.04 (m, 1H), 6.92 (s, 1H), 6.62 (d, 1H), 6.54 (d, 1H), 6.32 (d, 1H), 3.40-3.37 (m, 2H ), 3.17-3.11 (m, 3H), 2.33 (s, 3H), 2.08-2.05 (m, 1H), 1.72-1.69 (m, 1H) Example 30: Preparation of (R) -3,5-difluoro-4 - ((4-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.65 (s, 1H), 7.37 (d, 2H), 6.77-6.74 (m, 2H), 6.69 (d, 1H), 6 , 56-6.52 (m, 1H), 3.41-3.26 (m, 3H), 3.26-3.24 (m, 1H), 3.05-3.02 (m, 1H) , 2.48 (s, 3H), 2.20-2.18 (m, 1H), 1.83-1.81 (m, 1H)

Example 31: Preparation of (R) -5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4 -il) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.67 (s, 1H), 7.72 (d, 1H), 7.04 (t, 1H), 6.81 (d, 1H), 6.62 (t , 1H), 5.98 (d, 1H), 5.48 (s, 1H), 3.43-3.36 (m, 2H), 3.39-3.36 (m, 1H), 3, 30-3.26 (m, 2H), 2.36 (s, 3H), 2.36-2.10 (m, 1H), 1.77-1.73 (m, 1H) Example 32: Preparation of 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.68 (s, 1H), 7.73 (d, 1H), 7.06 (t, 1H), 6.83 (s, 1H), 6.64 (d , 1H), 6.57 (t, 1H), 6.01 (d, 1H), 3.50-3.40 (m, 3H), 3.28-3.23 (m, 2H), 2, 48 (s, 3H), 2.20-2.19 (m, 1H), 1.95-1.93 (m, 1H)

Example 33: Preparation of 4 - ((2- (3-aminopyrrolidin-1-yl) -4-fluorophenyl) amino) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.72 (s, 1H), 7.58 (t, 1H), 7.10 (t, 1H), 6.93 (m, 1H), 6.68 (d , 1H), 6.62 (d, 1H), 6.45 (d, 1H), 6.33 (d, 1H), 3.79 (m, 1H), 3.50 (m, 2H), 3 , 30 (m, 1H), 3.20 (m, 1H), 2.29 (m, 1H), 1.95 (m, 1H)

Example 34: Preparation of 4 - ((2- (3-aminopyrrolidin-1-yl) -4-fluorophenyl) amino) -3-chloro-N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.70 (d, 1H), 7.75 (s, 1H), 7.47 (d, 1H), 7.07 (t, 1H), 7.07 (t , 1H), 6.64 (d, 1H), 6.58 (t, 1H), 6.37 (d, 1H), 3.71 (m, 1H), 3.59 (m, 2H), 3 , 25 (m, 1H), 3.13 (m, 1H), 2.13 (m, 1H), 1.77 (m, 1H)

Example 35: Preparation of 4 - ((2- (3-aminopyrrolidin-1-yl) -4-fluorophenyl) amino) -5-chloro-2-fluoro-N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.72 (s, 1H), 7.74 (d, 1H), 7.10 (t, 1H), 6.98 (d, 1H), 6.68 (d , 1H), 6.63 (t, 1H), 6.06 (d, 1H), 3.73 (m, 1H), 3.53 (m, 2H), 3.24 (m, 2H), 2 , 23 (m, 1H), 1.87 (m, 1H)

Example 36: Preparation of 4 - ((2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.68 (s, 1H), 7.58 (d, 2H), 7.14 (d, 1H), 7.05 (t, 1H), 6.96 (d , 1H), 6.91-6.87 (m, 2H), 6.75 (d, 2H), 3.34-3.30 (m, 2H), 3.18-3.15 (m, 2H ), 3.00-2.97 (m, 1H), 2.35 (s, 3H), 2.15-2.12 (m, 1H), 1.75-1.71 (m, 1H) Example 37: Preparation of 2-fluoro-4 - ((2- (3- (methylamino) pyrrolidin-1-yl) -4- (trifluoromethyl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.69 (d, 1H), 7.65 (t, 1H), 7.35 (d, 1H), 7.20 (m, 2H), 6.87 (d , 1H), 6.74 (d, 1H), 6.66 (d, 1H), 3.65 (m, 1H), 3.47 (m, 1H), 3.37 (m, 2H), 3 , 03 (m, 1H), 2.60 (s, 3H), 2.30 (m, 1H), 2.02 (m, 1H)

Example 38: Preparation of 3-chloro-4 - ((2- (3- (methylamino) pyrrolidin-1-yl) -4- (trifluoromethyl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.67 (d, 1H), 7.80 (d, 1H), 7.53 (d, 1H), 7.25 (d, 1H), 7.17 (s , 1H), 7.13 (d, 1H), 6.89 (d, 1H), 6.59 (d, 1H), 3.35 (m, 2H), 3.28 (m, 1H), 3 , 12 (m, 2H), 2.37 (s, 3H), 2.11 (m, 1H), 1.75 (m, 1H)

Example 39: Preparation of 4 - ((4- (difluoromethoxy) -2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.69 (s, 1H), 7.58 (t, 1H), 7.12 (d, 1H), 6.70 (t, 1H), 6.66 (m , 2H), 6.50 (d, 1H), 6.38 (d, 1H), 3.59 (m, 1H), 3.41 (m, 2H), 3.32 (m, 1H), 3 , 12 (m, 1H), 2.54 (s, 3H), 2.24 (m, 1H), 1.93 (m, 1H)

Example 40: Preparation of 3-chloro-4 - ((4- (difluoromethoxy) -2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.69 (s, 1H), 7.76 (s, 1H), 7.47 (d, 1H), 7.09 (d, 1H), 6.81 (t , 2H), 6.65 (m, 2H), 6.39 (d, 1H), 3.40 (m, 3H), 3.18 (m, 2H), 2.44 (s, 3H), 2 , 15 (m, 1H), 1.81 (m, 1H)

Example 41: Preparation of (R) -4 - ((4-fluoro-2- (3-fluoropyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.68 (s, 1H), 7.54 (d, 2H), 7.02 (t, 1H), 6.92 (s, 1H), 6.60 (d , 1H), 6.52-6.49 (m, 3H), 3.57-3.53 (m, 1H), 3.49-3.46 (m, 1H), 3.26-3.21 (m, 3H), 2.10-2.06 (m, 1H), 2.00-1.94 (m, 1H)

Example 42: Preparation of (R) -2-fluoro-4 - ((4-fluoro-2- (3-fluoropyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.69 (s, 1H), 7.54 (t, 1H), 7.01 (t, 1H), 6.90 (d, 1H), 6.59 (t , 1H), 6.50 (d, 1H), 6.32 (d, 1H), 6.17 (d, 1H), 3.43-3.41 (m, 2H), 3.26-3, 21 (m, 2H), 2.21-1.94 (m, 3H)

Example 43: Preparation of (R) -3-chloro-4 - ((4-fluoro-2- (3-fluoropyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.69 (s, 1H), 7.73 (s, 1H), 7.44 (d, 1H), 7.04 (t, 1H), 6.92 (s , 1H), 6.61 (d, 1H), 6.53 (t, 1H), 6.28 (d, 1H), 3.47-3.41 (m, 3H), 3.26-3, 24 (m, 2H), 2.12-1.97 (m, 2H)

Example 44: Preparation of (R) -3,5-difluoro-4 - ((4-fluoro-2- (3-fluoropyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.73 (s, 1H), 7.34 (d, 2H), 7.04 (s, 1H), 6.92 (t, 1H), 6.57 (d , 1H), 6.47 (t, 1H), 3.56-3.25 (m, 4H), 3.13-3.11 (m, 1H), 2.04-1.99 (m, 2H )

Example 45: Preparation of (R) -5-chloro-2-fluoro-4 - ((4-fluoro-2- (3-fluoropyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl ) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.70 (s, 1H), 7.70 (d, 1H), 7.04 (t, 1H), 6.96 (d, 1H), 6.65 (d , 1H), 6.55 (t, 1H), 5.92 (d, 1H), 3.46-3.40 (m, 3H), 3.37-3.33 (m, 2H), 2, 15-1.96 (m, 2H)

Example 46: Preparation of 2-fluoro-4 - ((3-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.69 (d, 1H), 7.65 (t, 1H), 7.08 (lm, 2H), 6.88 (m, 3H), 6.74 (m , 1H), 3.56 (m, 1H), 3.37 (m, 2H), 3.34 (m, 1H), 3.17 (m, 1H), 3.16 (s, 3H), 2 , 35 (m, 1H), 2.05 (m, 1H)

Example 47: Preparation of 3-chloro-4 - ((3-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.67 (d, 1H), 7.84 (d, 1H), 7.63 (d, 1H), 7.19 (d, 1H), 7.05 (m , 2H), 6.87 (s, 1H), 6.79 (m, 1H), 3.60 (m, 1H), 3.52 (m, 1H), 3.33 (m, 1H), 3 , 26 (m, 1H), 3.20 (m, 1H), 2.56 (s, 3H), 2.27 (m, 1H), 1.90 (m, 1H)

Example 48: Preparation of 5-chloro-2-fluoro-4 - ((3-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide ,

1H NMR (500 MHz, MeOD): 8.65 (s, 1H), 7.81 (d, 1H), 7.10 (m, 1H), 7.05 (m, 1H), 6.84 (m , 3H), 3.53 (m, 3H), 3.25 (m, 2H), 2.56 (s, 3H), 2.26 (m, 1H), 1.91 (m, 1H)

Example 49: Preparation of 2-fluoro-4 - ((2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.68 (s, 1H), 7.57 (t, 1H), 7.14-7.09 (m, 2H), 6.97 (d, 1H), 6 , 92-6.90 (m, 1H), 6.84 (s, 1H), 6.55 (d, 1H), 6.40 (d, 1H), 3.42-3.41 (m, 1H ), 3.34-3.30 (m, 1H), 3.26-3.21 (m, 2H), 3.04-3.02 (m, 1H), 2.42 (s, 3H), 2.20-2.17 (m, 1H), 1.85-1.81 (m, 1H)

Example 50: Preparation of 3-chloro-4 - ((2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.66 (s, 1H), 7.76 (s, 1H), 7.48 (d, 1H), 7.15-7.10 (m, 2H), 6 , 96 (d, 1H), 6.89-6.86 (m, 1H), 6.83 (s, 1H), 6.52 (d 1H), 3.30-3.25 (m, 3H) , 3.11-3.07 (m, 2H), 2.34 (s, 3H), 2.10-2.07 (m, 1H), 1.73-1.69 (m, 1H) Example 51 : Preparation of 3,5-Difluoro-4 - ((2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.65 (s, 1H), 7.43 (d, 2H), 7.04 (d, 1H), 6.93-6.87 (m, 2H), 6 , 75 (s, 1H), 6.64 (d, 1H), 3.63-3.60 (m, 1H), 3.45-3.43 (m, 2H), 3.19-3.17 (m, 1H), 2.96-2.92 (m, 1H), 2.61 (s, 3H), 2.32-2.28 (m, 1H), 1.98-1.95 (m , 1H) Example 52: Preparation of 5-chloro-2-fluoro-4 - ((2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.66 (s, 1H), 7.74 (d, 1H), 7.20 (t, 1H), 7.12 (d, 1H), 6.96 (d , 1H), 6.92-6.89 (m, 1H), 6.79 (s, 1H), 6.12 (d, 1H), 3.30 (s, 3H), 3.16-3, 11 (m, 2H), 2.40 (s, 3H), 2.15-2.12 (m, 1H), 1.79-1.78 (m, 1H)

Example 53: Preparation of 2-fluoro-4 - ((4-methoxy-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.71 (s, 1H), 7.55 (t, 1H), 7.02 (d, 1H), 6.89 (s, 1H), 6.49 (m , 3H), 6.33 (d, 1H), 3.78 (s, 3H), 3.67 (m, 1H), 3.42 (m, 1H), 3.38 (m, 2H), 3 , 10 (m, 1H), 2.58 (s, 3H), 2.27 (m, 1H), 1.99 (m, 1H)

Example 54: Preparation of 3-chloro-4 - ((4-methoxy-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.70 (d, 1H), 7.74 (d, 1H), 7.45 (d, 1H), 7.00 (d, 1H), 6.94 (d , 1H), 6.49 (m, 2H), 6.37 (d, 1H), 3.78 (s, 3H), 3.47 (m, 1H), 3.38 (m, 2H), 3 , 27 (m, 1H), 3.16 (m, 1H), 2.46 (s, 3H), 2.17 (m, 1H), 1.83 (m, 1H)

Example 55: Preparation of 5-chloro-2-fluoro-4 - ((4-methoxy-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.71 (d, 1H), 7.72 (d, 1H), 7.01 (d, 1H), 6.89 (d, 1H), 6.51 (m , 2H), 6.48 (d, 1H), 3.81 (s, 3H), 3.67 (m, 1H), 3.45 (m, 3H), 3.20 (m, 1H), 2 , 59 (s, 3H), 2.27 (m, 1H), 1.96 (m, 1H)

Example 56: Preparation of (R) -4 - ((4-methoxy-2- (3- (methylamino) piperidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.68 (s, 1H), 7.59 (d, 2H), 7.13 (d, 1H), 6.93 (s, 1H), 6.78 (d , 2H), 6.62 (d, 2H), 3.77 (s, 3H), 3.25 (m, 1H), 2.87-2.65 (m, 4H), 2.39 (s, 3H), 1.85 (m, 1H), 1.70 (m, 1H), 1.54 (m, 2H)

Example 57: Preparation of (R) -2-fluoro-4 - ((4-methoxy-2- (3- (methylamino) piperidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.70 (s, 1H), 7.58 (t, 1H), 7.12 (d, 1H), 6.88 (s, 1H), 6.65-6 , 58 (m, 3H), 6.49 (d, 1H), 3.78 (s, 3H), 3.25 (m, 1H), 2.89-2.77 (m, 4H), 2, 47 (s, 3H), 1.88 (m, 2H), 1.46 (m, 2H)

Example 58: Preparation of (R) -3-chloro-4 - ((4-methoxy-2- (3- (methylamino) piperidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.68 (s, 1H), 7.77 (s, 1H), 7.51 (d, 1H), 7.17 (d, 1H), 6.90 (s , 1H), 6.72 (d, 1H), 6.67 (d, 2H), 3.78 (s, 3H), 2.96-2.94 (m, 1H), 2.70-2, 45 (m, 3H), 2.33 (s, 3H), 1.88 (m, 1H), 1.68 (m, 1H), 1.44-1.37 (m, 3H) Example 59: Preparation de (R) -3,5-difluoro-4 - ((4-methoxy-2- (3- (methylamino) piperidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.68 (s, 1H), 7.40 (d, 2H), 6.80 (t, 2H), 6.63 (s, 1H), 6.56 (d , 1H), 3.74 (s, 3H), 2.90-2.70 (m, 4H), 2.53 (s, 3H), 1.86-1.28 (m, 5H)

Example 60: Preparation of (R) -5-chloro-2-fluoro-4 - ((4-methoxy-2- (3- (methylamino) piperidin-1-yl) phenyl) amino) -N- (thiazol-4 -il) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.68 (s, 1H), 7.74 (d, 1H), 7.15 (d, 1H), 6.81 (s, 1H), 6.69 (d , 2H), 6.31 (d, 1H), 3.79 (s, 3H), 2.99 (m, 1H), 2.67-2.49 (m, 3H), 2.39 (s, 3H), 1.88 (m, 1H), 1.68 (m, 1H), 1.35-1.28 (m, 3H)

Example 61: Preparation of 3-chloro-4 - ((4-fluoro-2- (4-methylpiperazin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.70 (s, 1H), 7.81 (s, 1H), 7.54 (d, 1H), 7.24 (d, 1H), 7.00 (s , 1H), 6.89-6.79 (m, 3H), 2.98-2.92 (m, 4H), 2.37 (m, 4H), 2.20 (s, 3H)

Example 62: Preparation of 5-chloro-2-fluoro-4 - ((4-fluoro-2- (4-m ethylpiperazin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.71 (s, 1H), 7.77 (d, 1H), 7.24 (t, 1H), 6.98 (s, 1H), 6.91-6 , 82 (m, 2H), 6.40 (d, 1H), 2.96 (m, 4H), 2.36 (m, 4H), 2.15 (s, 3H)

Example 63: Preparation of (S) -5-chloro-4 - ((2- (3- (dimethylamino) pyrrolidin-1-yl) -4-fluorophenyl) amino) -2-fluoro-N- (thiazol-4- yl) benzenesulfonamide

1H NMR (500 MHz, CDCls): 8.62 (d, 1H), 7.79 (d, 1H), 6.98 (m, 2H), 6.52 (m, 2H), 6.23 (m , 2H), 3.22 (m, 3H), 3.14 (m, 1H), 2.70 (m, 1H), 2.23 (s, 6H), 1.78 (m, 2H)

Example 64: Preparation of (S) -5-chloro-4 - ((2- (3- (dimethylamino) pyrrolidin-1-yl) -4- (trifluoromethyl) phenyl) amino) -2-fluoro-N- (thiazole -4-yl) benzenesulfonamide

1H NMR (500 MHz, CDCI ³ ): 8.63 (s, 1H), 7.83 (d, 1H), 7.17 (m, 3H), 6.99 (s, 1H), 6.64 ( s, 1H), 6.56 (d, 1H), 3.25 (m, 4H), 2.81 (m, 1H), 2.24 (s, 6H), 1.85 (m, 2H)

Example 65: Preparation of 5-chloro-2-fluoro-4 - ((2- (4-methylpiperazin-1-yl) -4- (trifluoromethyl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.71 (s, 1H), 7.72 (d, 1H), 7.28 (m, 3H), 6.06 (s, 1H), 6.06 (d , 1H), 3.37 (m, 4H), 2.66 (m, 4H), 2.37 (s, 3H)

Example 66: Preparation of 5-chloro-4 - ((4- (difluoromethoxy) -2- (4-methylpiperazin-1-yl) phenyl) amino) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.72 (s, 1H), 7.78 (s, 1H), 7.28 (d, 1H), 6.98-6.82 (m, 4H), 6 , 49 (d, 1H), 3.39-3.30 (m, 4H), 2.97 (m, 4H), 2.25 (s, 3H)

Example 67: Preparation of 5-chloro-2-fluoro-4 - ((2- (4-methylpiperazin-1-yl) -4- (trifluoromethoxy) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.71 (s, 1H), 7.81 (d, 1H), 7.35 (d, 1H), 7.03-6.98 (m, 3H), 6 , 59 (d, 1H), 4.09 (d, 1H), 2.97 (m, 4H), 2.42 (m, 4H), 2.22 (s, 3H)

Example 68: Preparation of (S) -3-chloro-4 - ((2- (3- (dimethylamino) pyrrolidin-1-yl) -4- (trifluoromethyl) phenyl) amino) -N- (thiazol-4-yl ) benzenesulfonamide

1H NMR (500 MHz, CDCI ³ ): 8.66 (d, 1H), 7.80 (d, 1H), 7.52 (dd, 1H), 7.28 (s, 1H), 7.14 ( m, 2H), 7.05 (d, 1H), 6.89 (d, 1H), 6.64 (s, 1H), 3.22 (m, 2H), 3.16 (m, 2H), 2.79 (m, 1H), 2.23 (s, 6H), 2.10 (m, 1H), 2.06 (m, 1H)

Example 69: Preparation of (S) -2-fluoro-4 - ((4-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.70 (d, 1H), 7.56 (t, 1H), 7.06 (t, 1H), 6.90 (d, 1H), 6.65 (d , 1H), 6.57 (t, 1H), 6.43 (d, 1H), 6.30 (d, 1H), 3.37 (m, 3H), I 3.24 (m, 1H), 3.13 (m, 1H), 2.44 (S, 3H), 2.18 (m, 1H), 2.00 (m, 1H)

Example 70: Preparation of (S) -5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4 -il) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.71 (s, 1H), 7.73 (d, 1H), 7.07 (t, 1H), 6.92 (s, 1H), 6.67 (d , 1H), 6.59 (t, 1H), 6.01 (d, 1H), 3.45 (m, 3H), 3.23 (m, 2H), 2.46 (s, 3H), 2 , 17 (m, 1H), 1.83 (m, 1H)

Example 71: Preparation of (S) -5-chloro-4 - ((2- (3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) amino) -2-fluoro-N- (thiazole-4- yl) benzenesulfonamide

1H NMR (500 MHz, CDCls): 8.58 (d, 1H), 7.76 (d, 1H), 6.99 (m, 2H), 6.37 (m, 2H), 6.26 (m , 2H), 3.80 (s, 3H), 3.25-3.21 (m, 5H), 2.76 (m, 1H), 2.21 (s, 6H), 2.05 (m, 1 HOUR)

Example 72: Preparation of (S) -5-chloro-4 - ((4- (difluoromethoxy) -2- (3- (dimethylamino) pyrrolidin-1-yl) phenyl) amino) -2-fluoro-N- (thiazole -4-yl) benzenesulfonamide

1H NMR (500 MHz, CDCI ³ ): 8.63 (d, 1H), 7.79 (d, 1H), 7.04 (m, 1H), 6.96 (d, 1H), 6.57 ( m, 2H), 6.50 (d, 1H), 6.29 (m, 2H), 3.22 (m, 4H), 2.75 (m, 1H), 2.22 (s, 6H), 2.05 (m, 1H), 1.78 (m, 1H)

Example 73: Preparation of (R) -5-chloro-4 - ((2- (3- (dimethylamino) pyrrolidin-1-yl) -4-fluorophenyl) amino) -2-fluoro-N- (thiazol-4- yl) benzenesulfonamide

1H NMR (500 MHz, CDCh): 8.64 (s, 1H), 7.79 (d, 1H), 7.01 (t, 1H), 6.98 (s, 1H), 6.51 (m , 2H), 6.23 (m, 2H), 3.24 (m, 5H), 2.71 (m, 1H), 2.20 (s, 6H), 1.77 (m, 1H)

Example 74: Preparation of (R) -5-chloro-4 - ((2- (3- (dimethylamino) pyrrolidin-1-yl) -4- (trifluoromethyl) phenyl) amino) -2-fluoro-N- (thiazole -4-yl) benzenesulfonamide

1H NMR (500 MHz, CDCh): 8.64 (d, 1H), 7.84 (d, 1H), 7.24 (d, 1H), 7.12 (m, 2H), 6.98 (d , 1H), 6.66 (s, 1H), 6.54 (d, 1H), 3.23 (m, 4H), 2.83 (m, 1H), 2.23 (s, 6H), 1 , 90 (m, 2H)

Example 75: Preparation of (R) -5-chloro-4 - ((4- (difluoromethoxy) -2- (3- (dimethylamino) pyrrolidin-1-yl) phenyl) amino) -2-fluoro-N- (thiazole -4-yl) benzenesulfonamide

1H NMR (500 MHz, CDCh): 8.62 (d, 1H), 7.79 (d, 1H), 7.05 (d, 1H), 6.98 (d, 1H), 6.57 (s , 1H), 6.50 (t, 1H), 6.31 (m, 2H), 3.24 (m, 3H), 3.15 (m, 1H), 2.74 (m, 1H), 2 , 21 (s, 6H), 1.77 (m, 2H)

Example 76: Preparation of 4 - ((2- (1,4-diazepan-1-yl) -4-fluorophenyl) amino) -5-chloro-2-fluoro-N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.69 (s, 1H), 7.76 (d, 1H), 7.20 (m, 1H), 6.97 (d, 1H), 6.92 (s , 1H), 6.82 (t, 1H), 6.22 (d, 1H), 3.30 (m, 2H), 3.20 (t, 2H), 3.10 (m, 4H), 1 , 95 (m, 2H)

Example 77: Preparation of 5-chloro-4 - ((4-cyano-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.69 (s, 1H), 7.80 (d, 1H), 7.29 (s, 1H), 7.24 (m, 2H), 6.90 (s , 1H), 6.33 (d, 1H), 3.42 (m, 3H), 3.16 (m, 2H), 2.47 (s, 3H), 2.18 (m, 1H), 1 , 85 (m, 1H)

Example 78: Preparation of (R) -N- (1- (2 - ((2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfam oil) phenyl) amino) -5- (trifluoromethyl) phenyl) pyrrolidin-3-yl) acetamide

1H NMR (500 MHz, CDCls): 9.25 (broad, 1H), 8.64 (d, 1H), 7.84 (d, 1H), 7.18 (m, 2H), 7.02 (d , 1H), 6.69 (s, 1H), 6.52 (d, 1H), 5.60 (d, 1H), 4.50 (m, 1H), 3.37 (m, 1H), 3 , 27 (m, 1H), 3.09 (m, 2H), 2.27 (m, 1H), 1.95 (s, 3H), 1.77 (m, 1H) Example 79: Preparation of (R ) -N- (1- (2 - ((2-chloro-4- (N- (thiazol-4-yl) sulfamoyl) phenyl) amino) -5- (trifluoromethyl) phenyl) pyrrolidin-3-yl) acetamide

1H NMR (500 MHz, CDCls): 9.34 (s, 1H), 8.69 (d, 1H), 7.79 (d, 1H), 7.52 (d, 1H), 7.28 (d , 1H), 7.18 (m, 2H), 7.07 (s, 1H), 6.86 (d, 1H), 6.69 (s, 1H), 5.59 (d, 1H), 4 , 51 (m, 1H), 3.49 (s, 3H), 3.33 (m, 1H), 3.26 (m, 1H), 3.06 (m, 2H), 2.27 (m, 1H), 1.94 (s, 3H), 1.75 (m, 1H)

Example 80: Preparation of (S) -3-chloro-4 - ((2- (3- (methylamino) pyrrolidin-1-yl) -4- (trifluoromethyl) phenyl) amino) -N- (thiazol-4-yl ) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.70 (s, 1H), 7.82 (s, 1H), 7.55 (d, 1H), 7.23 (m, 3H), 6.95 (s , 1H), 6.69 (d, 1H), 3.60 (m, 1H), 3.44 (m, 2H), 3.30 (m, 1H), 3.15 (m, 1H), 2 , 57 (s, 3H), 2.24 (m, 1H), 1.94 (m, 1H

Example 81: Preparation of (S) -5-chloro-2-fluoro-4 - ((2- (3- (methylamine) pyrrolidin-1-yl) -4- (trifluoromethyl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.65 (s, 1H), 7.77 (d, 1H), 7.24 (d, 1H), 7.19 (s, 1H), 7.16 (d , 1H), 6.74s, 1H), 6.24 (d, 1H), 3.57 (m, 1H), 3.45 (m, 2H), 3.30 (m, 1H), 3.17 (m, 1H), 2.54 (s, 3H), 2.22 (m, 1H), 1.93 (m, 1H)

Example 82: Preparation of 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamino) acetidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.86 (s, 1H), 8.17 (s, 1H), 7.07 (d, 1H), 6.84 (d, 1H), 6.79 (d, 1H ), 6.40 (m, 1H), 6.33 (s, 1H), 3.93-3.70 (m, 4H), 3.35 (m, 1H), 3.23 (s, 3H)

Example 83: Preparation of 4 - ((2- (3-am inoacetidin-1-yl) -4-fluorophenyl) amino) -5-chloro-2-fluoro-N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.84 (s, 1H), 8.07 (s, 1H), 7.11 (d, 1H), 6.85 (d, 1H), 6.81 (d, 1H ), 6.40 (m, 1H), 6.33 (s, 1H), 4.03-3.82 (m, 4H), 3.42 (m, 1H)

Example 84: Preparation of 5-chloro-4 - ((2- (3- (dimethylamino) acetidin-1-yl) -4-fluorophenyl) amino) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, MeOD): 8.76 (s, 1H), 8.10 (s, 1H), 7.07 (d, 1H), 6.84 (d, 1H), 6.79 (d , 1H), 6.40 (m, 1H), 6.33 (s, 1H), 3.99-3.65 (m, 4H), 3.33 (m, 1H), 3.12 (s, 6H)

Example 85: Preparation of N- (1- (2 - ((2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenyl) amino) -5-fluorophenyl) acetidin-3 -il) acetamide

1H NMR (500 MHz, MeOD): 8.56 (s, 1H), 8.00 (s, 1H), 7.00 (d, 1H), 6.77 (d, 1H), 6.71 (d , 1H), 6.30 (m, 1H), 6.29 (s, 1H), 3.91-3.55 (m, 4H), 3.35 (m, 1H), 2.13 (s, 3H)

Example 86: Preparation of 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3-methoxypyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, CDCls): 10.93 (s, 1H), 8.74 (d, 1H), 7.81 (d, 1H), 6.99 (t, 1H), 6.50 (m , 2H), 6.24 (m, 2H), 3.92 (t, 1H), 3.32 (m, 2H), 3.26 (s, 3H), 3.11 (m, 2H), 2 .01 (m, 1H), 1.92 (m, 1H), 1.69 (m, 1H)

Example 87: Preparation of 5-chloro-2-fluoro-4 - ((2- (3-methoxypyrrolidin-1-yl) -4- (trifluoromethyl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, CDCls): 10.79 (s, 1H), 8.74 (d, 1H), 7.85 (d, 1H), 7.25 (m, 2H), 7.15 (s , 1H), 7.11 (d, 1H), 6.94 (d, 1H), 6.66 (s, 1H), 6.56 (d, 1H), 3.97 (t, 1H), 3 , 31 (m, 2H), 3.30 (s, 3H), 3.12 (m, 2H), 2.04 (m, 2H)

Example 88: Preparation of (R) -N- (1- (2 - ((2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfam oil) phenyl) amino) -5- fluorophenyl) pyrrolidin-3-yl) acetamide

1H NMR (500 MHz, CDCI ³ ): 10.63 (s, 1H), 8.70 (d, 1H), 7.78 (d, 1H), 7.01 (m, 1H), 6.94 ( d, 1H), 6.51 (m, 2H), 6.30 (s, 1H), 6.17 (d, 1H), 5.78 (d, 1H), 4.44 (m, 1H), 3, 38 (m, 1H), 3.27 (m, 1H), 3.10 (m, 1H), 3.03 (m, 1H), 2.15 (m, 1H), 1.90 (s, 3H ), 1.75 (m, 1H)

Example 89: Preparation of 3-chloro-4 - ((4-fluoro-2- (3-methoxypyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, CDCls): 10.74 (s, 1H), 8.77 (s, 1H), 7.72 (s, 1H), 7.42 (d, 1H), 7.01 (m , 2H), 6.53 (m, 3H), 6.18 (s, 1H), 3.90 (s, 1H), 3.34 (m, 2H), 3.25 (s, 3H), 3 , 12 (m, 2H), 1.99 (m, 1H), 1.89 (m, 1H)

Example 90: Preparation of 3-chloro-4 - ((2- (3-methoxypyrrolidin-1-yl) -4- (trifluoromethyl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

1H NMR (500 MHz, CDCls): 10.38 (s, 1H), 8.76 (s, 1H), 7.78 (s, 1H), 7.50 (d, 1H), 7.26 (d , 1H), 7.14 (m, 2H), 7.02 (s, 1H), 6.91 (d, 1H), 6.65 (s, 1H), 3.97 (s, 1H), 3 , 33 (m, 5H), 3.12 (m, 2H), 2.03 (m, 2H)

Example 91: Preparation of (R) -N- (1- (2 - ((2-chloro-4- (N- (thiazol-4-yl) sulfam oil) phenyl) amino) -5-fluorophenyl) pyrrolidine- 3-yl) acetamide

1H NMR (500 MHz, CDCI ³ ): 10.43 (broad, 1H), 8.76 (s, 1H), 7.71 (s, 1H), 7.41 (s, 1H), 7.03 (s , 2H), 6.54 (m, 3H), 6.25 (s, 1H), 5.90 (s, 1H), 4.40 (s, 1H), 3.28 (m, 2H), 2.98 (m, 3H), 2.15 (m, 1H), 2.03-1.74 (m, 3H)

Example 92: Preparation of 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide hydrochloride

Step 1) Preparation of tert-butyl (2 - ((2-amino-5-fluorophenyl) (methyl) amino) ethyl) (methyl) carbamate (iii)

2,4-Difluoro-1-nitrobenzene (i, 2.0 g, 12.6 mmol) and tert-butylmethyl (2- (methylamino) ethyl) carbamate (ii, 2.4 g, 1.0 eq.) Are dissolved in DMF (20 mL), and then K ² CO ³ (2.6 g, 1.5 eq.) was added thereto. While maintaining the internal temperature at 60 to 70 ° C, the reaction mixture was stirred for 2 hours. When the reaction solution turned dark yellow, the completion of the reaction was confirmed by TLC. After cooling to room temperature, EA / H ²⁰ was added and stirred, and then the layers were separated. MgSO4 was added to the separated organic layer, which was stirred, filtered, and then dried. The filtrate was concentrated under reduced pressure, and the residue was dissolved in MeOH (0.13g, 0.1eq.) And then Pd / C (0.13g, 0.1eq.) Was added. The interior was replaced with hydrogen gas, and the reaction mixture was stirred at room temperature for 6 hours. When the yellow color of the reaction solution faded and became almost colorless, the completion of the reaction was confirmed by TLC. The metal catalyst was filtered through Celite. The filtrate was concentrated under reduced pressure, and the obtained residue was separated by column chromatography (Hx / EA = 3/1) to obtain the objective compound (iii, 2.5 g, 66.9%).

1H NMR (500 MHz, CDCla): 6.76 (d, 1H), 6.64 (m, 2H), 3.36 (m, 2H), 2.94 (m, 2H), 2.86 (m , 3H), 2.68 (s, 3H), 1.45 (s, 9H)

Step 2) Preparation of tert-butyl thiazol-4-yl carbamate (v)

thiazole-4-carboxylic acid (iv, 5.0 g, 38.8 mmol) was dissolved in t-BuOH (100 mL), and then TEA (8.1 mL, 1.5 eq.) and DPPA (7.1 mL , 1.5 eq.) Were added thereto. While maintaining the internal temperature at 90 to 100 ° C, the reaction mixture was stirred for 3 days, and then the completion of the reaction was confirmed by TLC. The reaction was concentrated under reduced pressure, to which H ² O (50 mL) was added and extracted twice with ethyl acetate (EA, 100 mL). MgSO4 was added to the organic layer, which was stirred, filtered, and dried. The filtrate was concentrated under reduced pressure, and the residue was added to a small amount of EA and suspended. The resulting solid was filtered to obtain a white title compound (v, 4.0 g, 51.5%).

1H NMR (500 MHz, MeOD): 8.73 (s, 1H), 7.24 (s, 1H), 1.52 (s, 9H)

Step 3) Preparation of tert-butyl ((4-bromo-5-chloro-2-fluorophenyl) sulfonyl) (thiazol-4-yl) carbamate (vii)

Tert-butyl thiazol-4-yl carbamate (v, 4.0 g, 20.0 mmol) was added to a reaction vessel and the interior of the vessel was replaced with nitrogen gas. After dissolving in THF (32 mL), the solution was cooled to -78 ° C using dry ice-acetone. After cooling, LiHMDS (22.4 mL, 1.5 eq.) Was added slowly and the reaction mixture was stirred for 30 minutes. Then, 4-bromo-5-chloro-2-fluorobenzenesulfonyl chloride (vi, 6.0 g, 1.0 eq.) Was dissolved in THF (10 mL) and then slowly added to the reaction solution. The reaction mixture was stirred overnight and completion of the reaction was confirmed by TLC. H ² O (50 mL) was added and extracted twice with ethyl acetate (EA, 100 mL). MgSO4 was added to the organic layer, which was stirred, filtered, and dried. The filtrate was concentrated under reduced pressure, and the residue was crystallized from THF / n-hexane to obtain the title compound (vii, 4.4 g, 59.0%).

1H NMR (500 MHz, MeOD): 9.00 (s, 1H), 8.22 (d, 1H), 7.90 (d, 1H), 7.78 (s, 1H), 1.35 (s , 9H)

Step 4) Preparation of tert-butyl (2 - ((2 - ((4- (N- (tert-butoxycarbonyl) -N- (thiazol-4-yl) sulfamoyl) -2-chloro-5-fluorophenyl) amino) -5-fluorophenyl) (methyl) amino) ethyl (methyl) carbamate (viii)

Tert-butyl (2 - ((2-amino-5-fluorophenyl) (methyl) amino) ethyl (methyl) carbamate (iii, 10.0 g, 33.7 mmol) and tert-butyl ((4-bromo- 5 —Chloro-2-fluorophenyl) sulfonyl) (thiazol-4-yl) carbamate (vii, 13.0 g, 1.0 eq.) Were dissolved in 1,4-dioxane (200 mL).

Pd (OAc) ² (0.7 g, 0.1 eq.), Rac-BINAP (4.11 g, 0.2 eq.), And CS ² CO ³ (21.2 g, 2.0 eq.) were added to the reaction solution. While maintaining the internal temperature at 90 to 100 ° C, the reaction mixture was stirred for 5 hours, and then the completion of the reaction was confirmed by TLC. H ² O (100 mL) was added and extracted twice with ethyl acetate (EA, 1000 mL). MgSO4 was added to the organic layer, which was stirred, filtered, and then dried. The filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography using a mobile phase of EA / Hex = 1/4 to obtain the title compound (16.0 g, 69.1%).

1H NMR (500 MHz, MeOD): 8.95 (d, 1H), 7.96 (d, 1H), 7.68 (s, 1H), 7.26 (s, 1H), 6.95 (t, 1H ), 6.8 (s, 1H), 6.39 (s, 1H), 3.27 (s, 2H), 3.14 (s, 2H), 2.79 (s, 3H), 2.70 (d, 3H), 1.40 (s, 9H), 1.37 (s, 9H)

Step 5) Preparation of 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide hydrochloride

A tert-butyl (2 - ((2 - ((4- (N- (tert-butoxycarbonyl) -N- (thiazol-4-yl) sulfamoyl) -2-chloro-5-fluorophenyl) amino) -5-fluorophenyl ) (methyl) amino) ethyl (methyl) carbamate (vii, 14.0 g, 20.3 mmol) 1 M HCl in ethyl acetate (200 mL) was added. After stirring the mixture was stirred overnight while It was heated to 50 to 60 ° C, the completion of the reaction was confirmed by TLC. The reaction solution was filtered, and MC (200 mL) was added to the obtained residue and stirred for 1 hour. The resulting solid was filtered. to obtain the objective compound (9.1 g, 85.3%).

1H NMR (500 MHz, MeOD): 8.73 (d, 1H), 7.79 (d, 1H), 7.26 (dd, 1H), 7.03 (m, 2H), 6.90 (td , 1H), 6.43 (d, 1H), 3.26 (t, 2H), 3.09 (t, 2H), 2.70 (s, 3H), 2.65 (s, 3H)

Example 93: Preparation of 3-chloro-4 - ((2 - ((2- (dimethylamino) ethyl) (methyl) amino) -4-fluorophenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide

An intermediate product was prepared in the same manner as described in Example 92, except that N, N, N'-trimethylethane-1,2-diamine was used in place of tert-butyl methyl (2- (methylamino) ethyl) carbamate (ii) and 4-bromo-5-chlorobenzene sulfonyl chloride was used in place of 4-bromo-5-chloro-2-fluorobenzenesulfonyl chloride (vi). To the intermediate obtained tert-butyl ((3-chloro-4 - ((2 - ((- (dimethylamino) ethyl) (methyl) amino) -4-fluorophenyl) amino) phenyl) sulfonyl) (thiazol-4-yl) carbamate (0.05 g, 0.09 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 48.0%).

1H NMR (500 MHz, MeOD): 8.73 (s, 1H), 7.81 (s, 1H), 7.54 (d, 1H), 7.21 (dd, 1H), 7.00 (m , 2H), 6.82 (dd, 1H), 6.75 (d, 1H), 3.20 (t, 2H), 2.93 (t, 2H), 2.70 (s, 3H), 2 , 55 (s, 3H)

Example 94: Preparation of 5-chloro-4 - ((2 - ((2- (dimethylamino) ethyl) (methyl) amino) -4-fluorophenyl) amino) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide

An intermediate product was prepared in the same manner as described in Example 92, except that N, N, N'-trimethylethane-1,2-diamine was used in place of tert-butyl methyl (2- (methylamino) ethyl) carbamate (ii). To the intermediate obtained tert-butyl ((5-chloro-4 - ((2- (dimethylamino) ethyl) (methyl) amino) -4-fluorophenyl) amino) -2-fluorophenyl) sulfonyl) (thiazol-4-yl) carbamate (0.05 g, 0.08 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while heating to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 49.8%).

1H NMR (500 MHz, MeOD): 8.72 (s, 1H), 7.76 (d, 1H), 7.2 (t, 1H), 6.95 (m, 2H), 6.80 (t , 1H), 6.38 (d, 1H), 3.01 (t, 2H), 2.68 (s, 3H), 2.40 (t, 2H), 2.15 (s, 3H)

Example 95: Preparation of 5-chloro-2-fluoro-4 - ((2- (methyl (2- (methylamino) ethyl) amino) -4- (trifluoromethyl) phenyl) amino) -N- (thiazol-4-yl ) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 92, except that 2-fluoro-1-nitro-4- (trifluoromethyl) benzene was used in place of 2,4-difluoro-1-nitrobenzene (i) . To the intermediate obtained tert-butyl (2 - ((2 - ((4- (N- (tert-butoxycarbonyl) -N- (thiazol-4-yl) sulfamoyl) -2-chloro-5-fluorophenyl) amino) - 5- (trifluoromethyl) phenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 55.5%).

1H NMR (500 MHz, MeOD): 8.74 (s, 1H), 7.88 (d, 1H), 7.54 (s, 1H), 7.42 (m, 2H), 7.06 (s , 1H), 7.02 (d, 1H), 3.35 (t, 2H), 3.16 (t, 2H), 2.73 (s, 3H), 2.70 (s, 3H)

Example 96: Preparation of 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -N- (5-fluoropyrimidin-2-yl ) benzenesulfonamide hydrochloride

N- (2,4-dimethoxybenzyl) -5-fluoropyrimidin-2-amine (v) was prepared in place of Step 2 of Example 92. Especially, 2-chloro-5-fluoropyrimidine (iv, 0.48 g, 3 , 62 mmol), (2,4-dimethoxyphenyl) methanoamine (0.60 g, 1.0 eq.) And trimethylamine (0.76 mL, 1.5 eq.) Were dissolved in EtOH (10 mL). After stirring the mixture was stirred overnight while heating to 70-80 ° C, completion of the reaction was confirmed by TLC. The solution was concentrated under reduced pressure, and the obtained residue was separated by column chromatography using a mobile phase of EA / Hex = 1/2 to obtain 0.32 g (34% yield) of the target compound (v).

1H NMR (500 MHz, MeOD): 8.20 (s, 2H), 7.13 (d, 1H), 6.51 (s, 1H), 6.41 (d, 1H), 4.44 (s, 2H ), 3.82 (s, 3H), 3.76 (s, 3H) The target compound was prepared in the same way as described in Steps 1, 3, 4 and 5 of Example 92, except that N- ( 2,4-dimethoxybenzyl) -5-fluoropyrimidin-2-amine prepared above was used in place of tertbutylthiazol-4-ylcarbamate (v) in Example 92.

1H NMR (500 MHz, MeOD): 8.43 (m, 2H), 7.99 (t, 1H), 7.27 (dd, 1H), 7.03 (d, 1H), 6.88 (t , 1H), 6.45 (d, 1H), 3.20 (t, 2H), 3.10 (t, 2H), 2.71 (s, 3H), 2.67 (s, 3H)

Example 97: Preparation of 5-chloro-2-fluoro-N- (5-fluoropyrim idin-2-yl) -4 - ((2- (methyl (2- (methylamino) ethyl) amino) -4- (trifluoromethyl) ) phenyl) amino) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 96, except that 2-fluoro-1-nitro-4- (trifluoromethyl) benzene was used in place of 2,4-difluoro-1-nitrobenzene (i) . To the intermediate obtained tert-butyl (2 - ((2 - ((2-chloro-4- (N- (2,4-dimethoxybenzyl) -N- (5-fluoropyrimidin-2-yl) sulfamoyl) -5-fluorophenyl ) amino) -5- (trifluoromethyl) phenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.06 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 58.3%).

1H NMR (500 MHz, MeOD): 8.47 (s, 1H), 8.29 (s, 1H), 8.05 (m, 1H), 7.53 (d, 1H), 7.41 (m , 2H), 7.01 (t, 1h), 3.45 (t, 2H), 3.16 (t, 2H), 2.74 (s, 3H), 2.69 (s, 3H)

Example 98: Preparation of 5-chloro-4 - ((4- (difluoromethoxy) -2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -2-fluoro-N- (thiazol-4-yl ) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 92, except that 4 - (difluoromethoxy) -2-fluoro-1-nitrobenzene was used in place of 2,4-difluoro-1-nitrobenzene (i). To the intermediate obtained tert-butyl (2 - ((2 - ((4- (N- (tert-butoxycarbonyl) -N- (thiazol-4-yl) sulfamoyl) -2-chloro-5-fluorophenyl) amino) -5- (Difluoromethoxy) phenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 55.7%).

1H NMR (500 MHz, MeOD): 8.73 (s, 1H), 7.80 (d, 1H), 7.29 (d, 1H), 7.02 (s, 2H), 6.94 (d , 1H), 6.85 (t, 1H), 6.55 (d, 1H), 3.25 (t, 2H), 3.10 (t, 2H), 2.70 (s, 3H), 2 , 66 (s, 3H)

Example 99: Preparation of 5-chloro-4 - ((4-cyano-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 92, except that 3-fluoro-4-nitrobenzonitrile was used in place of 2,4-difluoro-1-nitrobenzene (i). To the intermediate obtained tert-butyl (2 - ((2 - ((4- (N- (tert-butoxycarbonyl) -N- (thiazol-4-yl) sulfamoyl) -2-chloro-5-fluorophenyl) amino) -5 cyanophenyl) (methyl) amino ) ethyl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 56.1%).

1H NMR (500 MHz, MeOD): 8.75 (s, 1H), 7.91 (d, 1H), 7.62 (d, 1H), 7.47 (t, 1H), 7.32 (d , 1H), 7.17 (d, 1H), 7.07 (d, 1H), 3.28 (t, 2H), 3.17 (t, 2H), 2.71 (s, 3H), 2 , 70 (s, 3H)

Example 100: Preparation of 5-chloro-4 - ((4-cyano-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -2-fluoro-N- (5-fluoropyrimidin-2-yl ) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 96, except that 3-fluoro-4-nitrobenzonitrile was used in place of 2,4-difluoro-1-nitrobenzene (i). To the intermediate obtained tert-butyl (2 - ((2 - ((2-chloro-4- (N- (2,4-dimethoxybenzyl) -N- (5-fluoropyrim idin-2-yl) sulfamoyl) -5- Fluorophenyl) amino) -5-cyanophenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 59.7%).

1H NMR (500 MHz, MeOD): 8.43 (s, 2H), 8.10 (d, 1H), 7.63 (s, 1H), 7.48 (d, 1H), 7.36 (d , 1H), 7.17 (d, 1H), 3.34-3.32 (m, 2H), 3.19-3.16 (m, 2H), 2.72 (s, 3H), 2, 71 (s, 3H)

Example 101: Preparation of 5-chloro-4 - ((4- (difluoromethoxy) -2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -2-fluoro-N- (5-fluoropyrimidin-2 -il) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 96, except that 4 - (difluoromethoxy) -2-fluoro-1-nitrobenzene was used in place of 2,4-difluoro-1-nitrobenzene (i). To the intermediate obtained tert-butyl (2 - ((2 - ((2-chloro-4- (N- (2,4-dimethoxybenzyl) -N- (5-fluoropyrim idin-2-yl) sulfamoyl) -5- Fluorophenyl) amino) -5- (difluoromethoxy) phenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.06 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02 g, 58.2%).

1H NMR (500 MHz, MeOD): 8.42 (s, 2H), 8.01 (d, 1H), 7.33-7.17 (m, 3H), 6.71 (d, 1H), 3 , 35-3.32 (m, 2H), 3.13-3.10 (m, 2H), 2.68 (s, 3H), 2.67 (s, 3H)

Example 102: Preparation of 5-chloro-2-fluoro-N- (5-fluoropyrim idin-2-yl) -4 - ((2- (methyl (2- (methyiamino) ethyl) amino) phenyl) amino) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 96, except that 1-fluoro-2-nitrobenzene was used in place of 2,4-difluoro-1-nitrobenzene (i). To the intermediate obtained tert-butyl (2 - ((2 - ((2-chloro-4- (N- (2,4-dimethoxybenzyl) -N- (5-fluoropyrim idin-2-yl) sulfamoyl) -5- Fluorophenyl) amino) phenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 60.7%).

1H NMR (500 MHz, MeOD): 8.42 (s, 2H), 8.00 (d, 1H), 7.30 (d, 1H), 7.03 (d, 1H), 6.94 (d , 1H), 6.69 (s, 1H), 6.52 (d, 1H), 3.34-3.32 (m, 2H), 3.12-3.10 (m, 2H), 2, 70 (s, 3H), 2.67 (s, 3H)

Example 103: Preparation of 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -N- (5-fluoropyridin-2-yl ) benzenesulfonamide hydrochloride

N- (2,4-dimethoxybenzyl) -5-fluoropyridin-2-amine (v) was prepared in place of Step 2 of Example 92. Specifically, 5-fluoropyridin-2-amine (iv, 0.55 g, 0 0.01 mmol) and 2,4-dimethoxybenzaldehyde (0.45 g, 0.9 eq.) Were dissolved in DCM (10 mL). After stirring at room temperature for 1 hour, sodium triacetoxyborohydroxide (1.0 g, 1 eq.) Was added three times at 15 minute intervals. After stirring the mixture was stirred overnight, completion of the reaction was confirmed by TLC. H ² O (10 mL) was added and extracted twice with dichloromethane (10 mL). MgSO4 was added to the organic layer, which was stirred, filtered, and dried. The filtrate was concentrated under reduced pressure, and then the resulting residue was separated by column chromatography using a mobile phase of EA / Hex = 1/4 to obtain 0.65 g (51% yield) of N- (2.4- dimethoxybenzyl) -5-fluoropyridine-2-amine (v).

1H NMR (500 MHz, CDCls): 7.90 (d, 1H), 7.16 (m, 2H), 6.46 (d, 1H), 6.41 (d, 1H), 6.34 (m , 1H), 4.36 (s, 2H), 3.81 (s, 3H), 3.77 (s, 3H)

The target compound was prepared in the same manner as described in Steps 1, 3, 4, and 5 of Example 92, except that N- (2,4-dimethoxybenzyl) -5-fluoropyridine-2-amine prepared above was used in instead of tertbutylthiazol-4-ylcarbamate (v) in Example 92.

1H NMR (500 MHz, MeOD): 8.05 (d, 1H), 7.89 (d, 1H), 7.51 (d, 1H), 7.26-6.87 (m, 4H), 6 , 42 (d, 1H), 3.38-3.25 (m, 2H), 3.10-3.09 (m, 2H), 2.69 (s, 3H), 2.65 (s, 3H )

Example 104: Preparation of 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -N- (pyridin-2-yl) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 103, except that pyridine-2-amine was used in place of 5-fluoropyridine-2-amine (iv). To the intermediate obtained tert-butyl (2 - ((5-chloro-2 - ((2-chloro-4- (N- (2,4-dimethoxybenzyl) -N- (pyridin-2-yl) sulfamoyl) -5 -fluorophenyl) amino) phenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 60.0%).

1H NMR (500 MHz, MeOD): 8.01-7.92 (m, 2H), 7.29-7.24 (m, 3H), 7.03 (d, 2H), 6.87 (d, 1H), 6.46 (d, 1H), 3.42-3.40 (m, 2H), 3.11-3.08 (m, 2H), 2.70 (s, 3H), 2.66 (s, 3H)

Example 105: Preparation of 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -N- (thiazol-2-yl) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 103, except that thiazolo-2-amine was used in place of 5-fluoropyridine-2-amine (iv). To the intermediate obtained tert-butyl (2 - ((5-chloro-2 - ((2-chloro-4- (N- (2,4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -5 -fluorophenyl) amino) phenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 59.8%).

1H NMR (500 MHz, MeOD): 7.84 (d, 2H), 7.28-7.04 (m, 3H), 6.89 (d, 1H), 6.74 (d, 1H), 6 , 46 (d, 1H), 3.26-3.24 (m, 2H), 3.11-3.08 (m, 2H), 2.71 (s, 3H), 2.66 (s, 3H )

Example 106: Preparation of 5-chloro-4 - ((4-cyano-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -2-fluoro-N- (5-fluoropyridin-2-yl ) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 103, except that 3-fluoro-4-nitrobenzonitrile was used in place of 2,4-difluoro-1-nitrobenzene (i). To the intermediate obtained tertbutyl (2 - ((2 - ((2-chloro-4- (N- (2,4-dimethoxybenzyl) -N- (5-fluoropyridin-2-yl) sulfamoyl) -5-fluorophenyl) ( methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL) .After stirring the mixture was stirred overnight while heating until 50 to 60 ° C, the completion of the reaction was confirmed by TLC The reaction solution was filtered to obtain the target compound (0.02 g, 56.0%).

1H NMR (500 MHz, MeOD): 8.05-8.01 (m, 2H), 7.62 (s, 1H), 7.55-7.46 (m, 2H), 7.33 (d, 1H), 7.14 (d, 1H), 3.34-3.32 (m, 2H), 3.18-3.17 (m, 2H), 2.72 (s, 3H), 2.71 (s, 3H)

Example 107: Preparation of 5-chloro-4 - ((4-cyano-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -2-fluoro-N- (pyridin-2-yl) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 103, except that 3-fluoro-4-nitrobenzonitrile was used in place of 2,4-difluoro-1-nitrobenzene (i), and pyridine-2-amine 5-fluoropyridin-2-amine (iv) was used instead. To the intermediate obtained tert-butyl (2 - ((2 - ((2-chloro-4- (N- (2,4-dimethoxybenzyl) -N- (pyridin-2-yl) sulfamoyl) -5-fluorophenyl) amino ) -5-cyanophenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 57.2%).

1H NMR (500 MHz, MeOD): 8.05 (d, 1H), 7.97-7.86 (s, 2H), 7.62 (s, 1H), 7.46 (d, 1H), 7 , 33-7.19 (m, 3H), 7.01-6.97 (m, 1H), 3.32-3.31 (m, 2H), 3.19-3.16 (m, 2H) , 2.72 (s, 3H), 2.71 (s, 3H)

Example 108: Preparation of 5-chloro-4 - ((4-cyano-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -2-fluoro-N- (thiazol-2-yl) benzenesulfonamide hydrochloride \

An intermediate product was prepared in the same manner as described in Example 103, except that 3-fluoro-4-nitrobenzonitrile was used in place of 2,4-difluoro-1-nitrobenzene (i), and thiazolo-2-amine 5-Fluoropyridin-2-amine (iv) was used instead. To the intermediate obtained tert-butyl (2 - ((2 - ((2-chloro-4- (N- (2,4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -5-fluorophenyl) amino ) -5-cyanophenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 60.2%).

1H NMR (500 MHz, MeOD): 7.96 (d, 1H), 7.62 (s, 1H), 7.46 (d, 1H), 7.28-7.14 (m, 3H), 6 , 77 (d, 1H), 3.32-3.30 (m, 2H), 3.20-3.17 (m, 2H), 2.72 (s, 3H), 2.71 (s, 3H )

Example 109: Preparation of 5-chloro-2-fluoro-N- (5-fluoropyridin-2-yl) -4 - ((2- (methyl (2- (methylamino) ethyl) amino) -4- (trifluoromethyl) phenyl) amino) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 103, except that 2-fluoro-1-nitro-4- (trifluoromethyl) benzene was used in place of 2,4-difluoro-1-nitrobenzene (i) . To the intermediate obtained tert-butyl (2 - ((2 - ((2-chloro-4- (N- (2,4-dimethoxybenzyl) -N- (5-fluoropyridin-2-yl) sulfamoyl) -5-fluorophenyl ) amino) -5- (trifluoromethyl) phenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.06 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming up to 50 ° C. 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02 g, 58.2%).

1H NMR (500 MHz, MeOD): 8.05 (d, 1H), 7.99 (d, 1H), 7.53 (m, 2H), 7.43 (s, 2H), 7.17 (m , 1H), 7.02 (d, 1H), 3.47 (t, 2H), 3.17 (t, 2H), 2.74 (s, 3H), 2.70 (s, 3H)

Example 110: Preparation of 5-chloro-2-fluoro-4 - ((2- (methyl (2- (methylamino) ethyl) amino) -4- (trifluoromethyl) phenyl) amino) -N- (pyridin-2-yl ) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 103, except that 2-fluoro-1-nitro-4- (trifluoromethyl) benzene was used in place of 2,4-difluoro-1-nitrobenzene (i) and pyridin-2-amine was used in place of 5-fluoropyridin-2-amine (iv). To the intermediate obtained tert-butyl (2 - ((2 - ((2-chloro-4- (N - (2, 4-dimethoxybenzyl) -N- (pyridin-2-yl) sulfamoyl-5-fluorophenyl) amino) -5- (trifluoromethyl) phenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.06 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC The reaction solution was filtered to obtain the target compound (0.02 g, 58.8%).

1H NMR (500 MHz, MeOD): 8.02 (d, 1H), 7.98 (t, 1H), 7.86 (t, 1H), 7.53 (s, 1H), 7.40 (m, 2H), 7.31 (d, 1H), 7.05 (d, 1H), 6.99 (m, 1H), 3.34 (t, 2H), 3.17 (t, 2H), 2, 74 (s, 3H), 2.71 (s, 3H)

Example 111: Preparation of 5-chloro-2-fluoro-4 - ((2- (methyl (2- (methylamino) ethyl) amino) -4- (trifluoromethyl) phenyl) amino) -N- (thiazol-2-yl ) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 103, except that 2-fluoro-1-nitro-4- (trifluoromethyl) benzene was used in place of 2,4-difluoro-1-nitrobenzene (i) and thiazol-2-amine was used in place of 5-fluoropyridine-2-amine (iv). To the intermediate obtained tert-butyl (2 - ((2 - ((2-chloro-4- (N - (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -5-fluorophenyl) amino ) -5- (trifluoromethyl) phenyl) (methyl) amino)

ethyl) (methyl) carbamate (0.05 g, 0.06 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 58.6%).

1H NMR (500 MHz, MeOD): 7.93 (d, 1H), 7.53 (s, 1H), 7.41 (m, 2H), 7.13 (d, 1H), 7.07 (d , 1H), 6.77 (d, 1H), 3.34 (t, 2H), 3.18 (t, 2H), 2.75 (s, 3H), 2.71 (s, 3H)

Example 112: Preparation of 5-chloro-2-fluoro-N- (5-fluoropyridin-2-yl) -4 - ((2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 103, except that 1-fluoro-2-nitrobenzene was used in place of 2,4-difluoro-1-nitrobenzene (i). To the intermediate obtained tert-butyl (2 - ((2 - ((2-chloro-4- (N- (2,4-dimethoxybenzyl) -N- (5-fluoropyridin-2-yl) sulfamoyl) -5-fluorophenyl ) amino) phenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 61.3%).

1H NMR (500 MHz, MeOD): 8.06 (d, 1H), 7.91 (d, 1H), 7.51 (m, 1H), 7.30 (m, 2H), 7.22 (t , 1H), 7.15 (m, 2H), 6.70 (d, 1H), 3.26 (t, 2H), 3.11 (t, 2H), 2.67 (s, 6H)

Example 113: Preparation of 5-chloro-2-fluoro-4 - ((2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -N- (pyridin-2-yl) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 103, except that 1-fluoro-2-nitrobenzene was used in place of 2,4-difluoro-1-nitrobenzene (i) and pyridine-2-amine was used instead of 5-fluoropyridin-2-amine (iv). To the intermediate obtained tert-butyl (2 - ((2 - ((2-chloro-4- (N- (2,4-dimethoxybenzyl) -N- (pyridin-2-yl) sulfamoyl) -5-fluorophenyl) amino ) Phenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 61.6%).

1H NMR (500 MHz, MeOD): 8.03 (d, 1H), 7.96 (d, 1H), 7.90 (d, 1H), 7.30 (t, 3H), 7.23 (t , 1H), 7.17 (t, 1H), 7.04 (m, 1H), 6.73 (d, 1H), 3.26 (t, 2H), 3.12 (t, 2H), 2 , 68 (s, 3H), 2.67 (s, 3H)

Example 114: Preparation of 5-chloro-2-fluoro-4 - ((2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -N- (thiazol-2-yl) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 103, except that 1-fluoro-2-nitrobenzene was used in place of 2,4-difluoro-1-nitrobenzene (i) and thiazol-2-amine was used. used instead of 5-fluoropyridin-2-amine (iv). To the intermediate obtained tert-butyl (2 - ((2 - ((2-chloro-4- (N- (2,4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -5-fluorophenyl) amino ) Phenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 61.3%).

1H NMR (500 MHz, MeOD): 7.86 (d, 1H), 7.30 (m, 2H), 7.20 (m, 2H), 7.12 (d, 1H), 6.75 (m , 2H), 3.26 (t, 2H), 3.12 (t, 2H), 2.70 (s, 3H), 2.68 (s, 3H)

Example 115: Preparation of 5-chloro-4 - ((4- (difluoromethoxy) -2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -2-fluoro-N- (5-fluoropyridin-2 -il) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 103, except that 4 - (difluoromethoxy) -2-fluoro-1-nitrobenzene was used in place of 2,4-difluoro-1-nitrobenzene (i). To the intermediate obtained tert-butyl (2 - ((2 - ((2-chloro-4- (N- (2,4-dimethoxybenzyl) -N- (5-fluoropyridin-2-yl) sulfamoyl) -5-fluorophenyl ) amino) -5- (difluoromethyl) phenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.06 mmol) was added 1 M h C i in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02 g, 58.2%).

1H NMR (500 MHz, MeOD): 8.06 (d, 1H), 7.90 (d, 1H), 7.52 (m, 1H), 7.29 (d, 1H), 7.16 (m , 1H), 7.02 (d, 1H), 6.94 (m, 1H), 6.84 (t, 1H), 6.53 (d, 1H), 3.26 (t, 2H), 3 , 10 (t, 2H), 2.70 (s, 3H), 2.66 (s, 3H)

Example 116: Preparation of 5-chloro-4 - ((4- (difluoromethoxy) -2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -2-fluoro-N- (thiazol-2-yl ) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 103, except that 4 - (difluoromethoxy) -2-fluoro-1-nitrobenzene was used in place of 2,4-difluoro-1-nitrobenzene (i) and Thiazol-2-amine was used in place of 5-fluoropyridine-2-amine (iv). To the intermediate obtained tert-butyl (2 - ((2 - ((2-chloro-4- (N - (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -5-fluorophenyl) amino ) -5- (Difluoromethoxy) phenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.06 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 58.7%).

1H NMR (500 MHz, MeOD): 7.85 (d, 1H), 7.29 (d, 1H), 7.11 (d, 1H), 7.03 (d, 1H), 6.94 (d , 1H), 6.85 (t, 1H), 6.75 (d, 1H), 6.58 (d, 1H), 3.23 (t, 2H), 3.12 (t, 2H), 2 , 72 (s, 3H), 2.67 (s, 3H)

Example 117: Preparation of 5-chloro-4 - ((4- (difluoromethoxy) -2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -2-fluoro-N- (pyridin-2-yl ) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 103, except that 4 - (difluoromethoxy) -2-fluoro-1-nitrobenzene was used in place of 2,4-difluoro-1-nitrobenzene (i) and pyridine-2-amine was used in place of 5-fluoropyridine-2-amine (iv). To the intermediate obtained tert-butyl (2 - ((2 - ((2-chloro-4- (N - (2, 4-dimethoxybenzyl) -N- (pyridine-2-yl) sulfamoyl) -5-fluorophenyl) amino ) -5- (Difluoromethoxy) phenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.06 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, the Completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 59.3%).

1H NMR (500 MHz, MeOD): 8.04 (d, 1H), 7.95 (d, 1H), 7.90 (t, 1H), 7.30 (m, 2H), 7.06 (m , 2H), 6.93 (d, 1H), 6.84 (t, 1H), 6.56 (d, 1H), 3.26 (t, 2H), 3.11 (t, 2H), 2 , 70 (s, 3H), 2.67 (s, 3H)

Example 118: Preparation of 5-chloro-2-fluoro-N- (5-fluoropyridin-2-yl) -4 - ((4-m ethoxy-2- (me-ethyl (2- (methiiamino) ethyl) amino) phenyl ) amino) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 103, except that 2-fluoro-4-methoxy-1-nitrobenzene was used in place of 2,4-difluoro-1-nitrobenzene (i). To the intermediate obtained tert-butyl (2 - ((2 - ((2-chloro-4- (N- (2,4-dimethoxybenzyl) -N- (5-fluoropyridin-2-yl) sulfamoyl) -5-fluorophenyl ) amino) -5- (methoxyphenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture stirred overnight while heating to 50-60 ° C, completion of the reaction was confirmed by TLC The reaction solution was filtered to obtain the target compound (0.02g, 59.5%).

1H NMR (500 MHz, MeOD): 8.05 (d, 1H), 7.86 (d, 1H), 7.53-7.50 (m, 1H), 7.18-7.14 (m, 2H), 6.80-6.73 (m, 2H), 6.35 (d, 1H), 3.82 (s, 3H), 3.25-3.23 (m, 2H), 3.09 -3.07 (m, 2H), 2.67 (s, 3H), 2.64 (s, 3H)

Example 119: Preparation of 5-chloro-2-fluoro-4 - ((4-methoxy-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -N- (thiazol-2-yl) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 103, except that 2-fluoro-4-methoxy-1-nitrobenzene was used in place of 2,4-difluoro-1-nitrobenzene (i) and thiazole- 2-amine was used in place of 5-fluoropyridine-2-amine (iv). To the intermediate obtained tert-butyl (2 - ((2 - ((2-chloro-4- (N - (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -5-fluorophenyl) amino ) -5-Methoxyphenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 60.0%).

1H NMR (500 MHz, MeOD): 7.81 (d, 1H), 7.20 (d, 1H), 7.11 (d, 1H), 6.81-6.73 (m, 3H), 6 , 40 (d, 1H), 3.82 (s, 3H), 3.30-3.28 (m, 2H), 3.25-3.24 (m, 2H), 2.69 (s, 3H ), 2.66 (s, 3H)

Example 120: Preparation of 5-chloro-2-fluoro-4 - ((4-methoxy-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 92, except that 2-fluoro-4-methoxy-1-nitrobenzene was used in place of 2,4-difluoro-1-nitrobenzene (i). To the intermediate obtained tert-butyl (2 - ((2 - ((4- (N- (tert-butoxycarbonyl) -N- (thiazol-4-yl) sulfamoyl) -2-chloro-5-fluorophenyl) amino) - 5-methoxyphenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 55.5%).

1H NMR (500 MHz, MeOD): 8.73 (d, 1H), 7.76 (d, 1H), 7.18 (d, 1H), 7.02 (d, 1H), 6.82 (d , 1H), 6.75 (d, 1H), 6.36 (d, 1H), 3.85 (s, 3H), 3.26-3.24 (m, 2H), 3.09-3, 07 (m, 2H), 2.69 (s, 3H), 2.64 (s, 3H)

Example 121: Preparation of 5-chloro-2-fluoro-4 - ((2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 92, except that 1-fluoro-2-nitrobenzene was used in place of 2,4-difluoro-1-nitrobenzene (i). To the intermediate obtained tert-butyl (2 - ((2 - ((4- (N- (tert-butoxycarbonyl) -N- (thiazol-4-yl) sulfamoyl) -2-chloro-5-fluorophenyl) amino) phenyl (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while heating up to 50 to 60 ° C, completion of the reaction was confirmed by TLC The reaction solution was filtered to obtain the target compound (0.02 g, 57.5%).

1H NMR (500 MHz, MeOD): 8.74 (d, 1H), 7.81 (d, 1H), 7.33-7.18 (m, 4H), 7.04 (d, 1H), 6 , 70 (d, 1H), 3.26-3.24 (m, 2H), 3.12-3.09 (m, 2H), 2.69 (s, 3H), 2.66 (s, 3H )

Example 122: Preparation of 5-chloro-2-fluoro-N- (5-fluoropyrim idin-2-yl) -4 - ((4-m ethoxy-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 96, except that 2-fluoro-4-methoxy-1-nitrobenzene was used in place of 2,4-difluoro-1-nitrobenzene (i). To the intermediate obtained tertbutyl (2 - ((2 - ((2-chloro-4- (N- (2,4-dimethoxybenzyl) -N- (5-fluoropyrimidin-2-yl) sulfamoyl) -5-fluorophenyl) amino ) -5-Methoxyphenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.06 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 59.5%).

1H NMR (500 MHz, MeOD): 8.42 (s, 2H), 7.96 (d, 1H), 7.18 (d, 1H), 6.82 (d, 1H), 6.76 (d , 1H), 6.36 (d, 1H), 3.81 (s, 3H), 3.27-3.25 (m, 2H), 3.17-3.08 (m, 2H), 2, 70 (s, 3H), 2.65 (s, 3H)

Example 123: Preparation of 5-chloro-4 - ((4-chloro-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 92, except that 4-chloro-2-fluoro-1-nitrobenzene was used in place of 2,4-difluoro-1-nitrobenzene (i). To the intermediate obtained tert-butyl (2 - ((2 - ((4- (N- (tert-butoxycarbonyl) -N- (thiazol-4-yl) sulfamoyl) -2-chloro-5-fluorophenyl) amino) - 5-chlorophenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 55.8%).

1H NMR (500 MHz, MeOD): 8.74 (s, 1H), 7.81 (d, 1H), 7.31-7.14 (m, 3H), 7.04 (d, 1H), 6 , 64 (d, 1H), 3.26-3.24 (m, 2H), 3.11-3.10 (m, 2H), 2.69 (s, 3H), 2.66 (s, 3H )

Example 124: Preparation of 5-chloro-4 - ((4-chloro-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -2-fluoro-N- (5-fluoropyrimidin-2-yl ) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 96, except that 4-chloro-2-fluoro-1-nitrobenzene was used in place of 2,4-difluoro-1-nitrobenzene (i). To the intermediate obtained tert-butyl (2 - ((5-chloro-2 - ((2-chloro-4- (N- (2,4-dimethoxybenzyl) -N- (5-fluoropyrim idin-2-yl) sulfamoyl ) -5-fluorophenyl) amino) phenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.06 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 59.3%).

1H NMR (500 MHz, MeOD): 8.42 (s, 2H), 8.01 (d, 1H), 7.27 (d, 2H), 7.15-7.13 (m, 1H), 6 , 64 (d, 1H), 3.27-3.25 (m, 2H), 3.13-3.11 (m, 2H), 2.70 (s, 3H), 2.67 (s, 3H )

Example 125: Preparation of 5-chloro-4 - ((4-chloro-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -2-fluoro-N- (5-fluoropyridin-2-yl ) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 103, except that 4-chloro-2-fluoro-1-nitrobenzene was used in place of 2,4-difluoro-1-nitrobenzene (i). To the intermediate obtained tert-butyl (2 - ((5-chloro-2 - ((2-chloro-4- (N- (2,4-dimethoxybenzyl) -N- (5-fluoropyridin-2-yl) sulfamoyl) -5-fluorophenyl) amino) phenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 59.3%).

1H NMR (500 MHz, MeOD): 8.06 (d, 1H), 7.91 (d, 1H), 7.54-7.50 (m, 2H), 7.27-7.13 (m, 4H), 6.63 (d, 1H), 3.27-3.25 (m, 2H), 3.11-3.09 (m, 2H), 2.69 (s, 3H), 2.66 (s, 3H)

Example 126: Preparation of 5-chloro-4 - ((4-chloro-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -2-fluoro-N- (thiazol-2-yl) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 103, except that 4-doro-2-fluoro-1-nitrobenzene was used in place of 2,4-difluoro-1-nitrobenzene (i) and thiazolo- 2-amine was used in place of 5-fluoropyridine-2-amine (iv). To the intermediate obtained tert-butyl (2 - ((5-chloro-2 - ((2-chloro-4- (N - (2,4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -5 -fluorophenyl) amino) phenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 59.8%).

1H NMR (500 MHz, MeOD): 7.87 (d, 1H), 7.27 (d, 2H), 7.15-7.12 (m, 2H), 6.75-6.68 (m, 2H), 3.26-3.25 (m, 2H), 3.13-3.10 (m, 2H), 2.71 (s, 3H), 2.68 (s, 3H)

Example 127: Preparation of 5-chloro-N- (5-chlorothiazol-2-yl) -2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 103, except that 5-chlorothiazol-2-amine was used in place of 5-fluoropyridine-2-amine (iv). To the intermediate obtained tert-butyl (2 - ((2 - ((2-chloro-4- (N- (5-chlorothiazol-2-yl) -N- (2,4-dimethoxybenzyl) sulfamoyl) -5-fluorophenyl ) amino) -5-fluorophenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.06 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 59.2%).

1H NMR (500 MHz, MeOD): 7.82 (d, 1H), 7.29 (d, 1H), 7.27 (s, 1H), 7.05 (d, 1H), 6.90 (t , 1H), 6.48 (d, 1H), 3.27-3.25 (m, 2H), 3.12-3.09 (m, 2H), 2.71 (s, 3H), 2, 67 (s, 3H)

Example 128: Preparation of 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -N- (5-fluorothiazol-2-yl ) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 103, except that 5-fluorothiazol-2-amine was used in place of 5-fluoropyridine-2-amine (iv). To the intermediate obtained tert-butyl (2 - ((2 - ((2-chloro-4- (N- (2,4-dimethoxybenzyl) -N- (5-fluorothiazol-2-yl) sulfamoyl) -5-fluorophenyl ) amino) -5-fluorophenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 59.8%).

1H NMR (500 MHz, MeOD): 7.82 (t, 1H), 7.30 (t, 1H), 7.05-6.91 (m, 3H), 6.48 (d, 1H), 3 , 27-3.25 (m, 2H), 3.12-3.10 (m, 2H), 2.72 (s, 3H), 2.67 (s, 3H)

Example 129: Preparation of 5-chloro-N- (5-chlorothiazol-2-yl) -2-fluoro-4 - ((2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 103, except that 5-chlorothiazol-2-amine was used in place of 5-fluoropyridin-2-amine (iv) and 1-fluoro-2-nitrobenzene 2,4-Difluoro-1-nitrobenzene (i) was used in place. To the intermediate obtained tert-butyl (2 - ((2 - ((2-chloro-4- (N - (5-chlorothiazol-2-yl) -N- (2,4-dimethoxybenzyl) sulfamoyl) -5-fluorophenyl ) amino) phenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 59.8%).

1H NMR (500 MHz, MeOD): 7.84 (d, 1H), 7.33 (d, 1H), 7.40 (d, 1H), 7.19 (m, 3H), 6.75 (d , 1H), 3.26 (t, 2H), 3.13 (t, 2H), 2.70 (s, 3H), 2.69 (s, 3H)

Example 130: Preparation of 5-chloro-N- (5-chlorothiazol-2-yl) -2-fluoro-4 - ((4-m ethoxy-2- (m ethyl (2- (methylamino) ethyl) amino) phenyl ) amino) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 103, except that 5-chlorothiazol-2-amine was used in place of 5-fluoropyridine-2-amine (iv) and 2-fluoro-4-methoxy- 1-nitrobenzene was used in place of 2,4-difluoro-1-nitrobenzene (i). To the intermediate obtained tert-butyl (2 - ((2 - ((2-c lo ro-4- (N - (5-chlorothiazol-2-yl) -N- (2,4-dimethoxybenzyl) sulfamoyl) -5 -fluorophenyl) amino) -5-methoxyphenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.06 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 58.7%).

1H NMR (500 MHz, MeOD): 7.79 (d, 1H), 7.20 (d, 1H), 7.19 (s, 1H), 6.80 (d, 1H), 6.75 (dd , 1H), 6.41 (d, 1H), 3.82 (s, 3H), 3.26 (t, 2H), 3.10 (t, 2H), 2.70 (s, 3H), 2 , 68 (s, 3H)

Example 131: Preparation of 5-chloro-2-fluoro-N- (5-fluorothiazol-2-yl) -4 - ((2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 103, except that 5-fluorothiazol-2-amine was used in place of 5-fluoropyridine-2-amine (iv) and 1-fluoro-2-nitrobenzene was used. used in place of 2,4-difluoro-1-nitrobenzene (i). To the intermediate obtained tert-butyl (2 - ((2 - ((2-chloro-4- (N - (2, 4-dimethoxybenzyl) -N- (5-fluorothiazol-2-yl) sulfamoyl) -5-fluorophenyl ) amino) phenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 60.5%).

1H NMR (500 MHz, MeOD): 7.84 (d, 1H), 7.31 (m, 2H), 7.22 (m, 2H), 7.00 (s, 1H), 6.76 (d , 1H), 3.27 (t, 2H), 3.13 (t, 2H), 2.70 (s, 3H), 2.69 (s, 3H)

Example 132: Preparation of 5-chloro-2-fluoro-N- (5-fluorothiazol-2-yl) -4 - ((4-m ethoxy-2- (methyl (2- (methylamino) ethyl) amino) phenyl) ) amino) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 103, except that 5-fluorothiazol-2-amine was used in place of 5-fluoropyridine-2-amine (iv) and 2-fluoro-4-methoxy- 1-nitrobenzene was used in place of 2,4-difluoro-1-nitrobenzene (i). To the intermediate obtained tert-butyl (2 - ((2 - ((2-chloro-4- (N - (2, 4-dimethoxybenzyl) -N- (5-fluorothiazol-2-yl) sulfamoyl) -5-fluorophenyl ) amino) -5-methoxyphenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 59.3%).

1H NMR (500 MHz, MeOD): 7.79 (t, 1H), 7.22 (t, 1H), 6.99 (s, 1H), 6.86 (d, 1H), 6.78 (dd , 1H), 6.40 (d, 1H), 3.83 (s, 3H), 3.34 (t, 2H), 3.11 (t, 2H), 2.75 (s, 3H), 2 , 67 (s, 3H)

Example 133: Preparation of 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -N- (5-methylisoxazol-3-yl ) benzenesulfonamide hydrochloride

Tert-butyl ((4-bromo-5-chloro-2-fluorophenyl) sulfonic) (5-methyloxazole-3-¡l) carbamate (vii) was prepared in place of Steps 2 and 3 of the Example 92. Specifically, 5-methylisoxazole-3-amine (iv, 1.00 g, 10.19 mmol), (4-bromo-5-chloro-2-fluorobenzenesulfonyl chloride (vi, 3.14 g, 1, 0 eq.) And pyridine (2.4 mL, 3.0 eq.) Were dissolved in DCM (25 mL) After stirring the mixture was stirred overnight, completion of the reaction was confirmed by TLC. ² O (30 mL) was added and extracted twice with dichloromethane (10 mL). MgSO4 was added to the reaction and extracted twice with ethyl acetate. MgSO4, was added to the organic layer, which was stirred, was added. filtered and then dried The filtrate was concentrated under reduced pressure, and then the resulting residue was separated by column chromatography using a mobile phase of EA / Hex = 1/1 to obtain 1.0 g (yield 27%) of the compound objective (v).

1H NMR (500 MHz, CDCls): 8.66 (d, 1H), 7.96 (d, 1H), 7.44 (d, 1H), 5.88 (broad, 1H), 2.33 (s , 3H)

The 4-bromo-5-chloro-2-fluoro-N- (5-methylisoxazol-3-yl) benzenesulfonamide (v, 1.00 g, 2.71 mmol) prepared above, N, N-dimethylaminopyridine (0.06 g, 0.2 eq.) and di-tert-butyl dicarbonate (1.1 mL, 2.0 eq.) were dissolved in tetrahydrofuran (20 mL). After stirring the reaction solution overnight at room temperature, and the completion of the reaction was confirmed by TLC. H ²⁰ (30 mL) was added to the reaction product, and the mixture was extracted twice with ethyl acetate. MgSO4 was added to the organic layer, which was stirred, filtered, and then dried. The filtrate was concentrated under reduced pressure, and the obtained residue was separated by column chromatography using a mobile phase of EA / Hex = 1/2 to obtain 0.40 g (31% yield) of the target compound (vii).

1H NMR (500 MHz, MeOD): 8.19 (d, 1H), 7.93 (d, 1H), 6.34 (s, 1H), 2.49 (s, 3H), 1.36 (s , 9H)

The target compounds were prepared in the same way as described in Steps 1, 4 and 5 of Example 1, except that tert-butyl ((4-bromo-5-chloro-2-fluorophenyl) sulfonyl) (5 -methylisoxazol-3-yl) carbamate (vii) prepared above.

1H NMR (500 MHz, MeOD): 7.8 (d, 1H), 7.34-7.31 (m, 2H), 7.25 (t, 1H), 7.21-7.19 (m, 1H), 6.71 (d, 1H), 6.07 (s, 1H), 2.70 (s, 3H), 2.67 (s, 3H), 2.32 (s, 3H)

Example 134: Preparation of 5-chloro-2-fluoro-4 - ((2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -N- (5-methylisoxazol-3-yl) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 133, except that 1-fluoro-2-nitrobenzene was used in place of 2,4-difluoro-1-nitrobenzene (i). To the intermediate obtained tert-butyl (2 - ((2 - ((4- (N- (tert-butoxycarbonyl) -N- (5-methylisoxazol-3-yl) sulfamoyl) -2-chloro-5-fluorophenyl) amino ) Phenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 65.6%).

1H NMR (500 MHz, MeOD): 7.79 (d, 1H), 7.21 (t, 1H), 7.00 (d, 1H), 6.98 (t, 1H), 6.41 (d , 1H), 5.85 (s, 1H), 3.24-3.23 (m, 2H), 3.05-3.03 (m, 2H), 2.69 (s, 3H), 2, 58 (s, 3H), 2.22 (s, 3H)

Example 135: Preparation of 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -N- (5-methyl-1H-pyrazole -3-yl) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 133, except that tertbutyl 3-amino-5-methyl-1H-pyrazolo-1-carboxylate was used in place of 5-methylisoxazole-3-amine (iv) . To the intermediate obtained tert-butyl 3 - ((N- (tert-butoxycarbonyl) -4- (2- (2 - ((tert-butoxycarbonyl) (methyl) amino) ethyl) (methyl) amino) -4-fluorophenyl) amino) -5-chloro-2-fluorophenyl) sulfonamido) -5-methyl-1H-pyrazolo-1-carboxylate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 64.7%).

1H NMR (500 MHz, MeOD): 7.86 (1H), 7.27 (t, 1H), 7.06 (d, 1H), 6.89 (t, 1H), 6.47 (d, 1H ), 6.08 (d, 1H), 3.15-3.12 (m, 2H), 2.71 (s, 3H), 2.67 (s, 3H), 2.34 (s, 3H)

Example 136: Preparation of 5-chloro-2-fluoro-4 - ((2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -N- (5-methyl-1H-pyrazol-3-yl ) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 133, except that tertbutyl 3-amino-5-methyl-1H-pyrazolo-1-carboxylate was used in place of 5-methylisoxazole-3-amine (iv) , and 1-fluoro-2-nitrobenzene was used in place of 2,4-difluoro-1-nitrobenzene (i). To the intermediate obtained tert-butyl 3 - ((N - (tert-butoxycarbonyl) -4- (2- (2 - ((tert-butoxycarbonyl) (methyl) amino) ethyl) (methyl) amino) phenyl) amino) - 5-chloro-2-fluorophenyl) sulfonamido) -5-methyl-1H-pyrazolo-1-carboxylate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 65.7%).

1H NMR (500 MHz, MeOD): 7.88 (d, 1H), 7.35-7.21 (m, 4H), 6.72 (d, 1H), 6.08 (s, 1H), 3 , 35-3.33 (m, 2H), 3.14-3.11 (m, 2H), 2.72 (s, 3H), 2.68 (s, 3H), 2.34 (s, 3H )

Example 137: Preparation of 5-chloro-4 - ((2 - ((2- (dimethylamino) ethyl) (methyl) amino) -4-fluorophenyl) amino) -2-fluoro-N- (5-fluoropyridin-2- yl) benzenesulfonamide hydrochloride

An intermediate (viii) was prepared in the same manner as described in Example 103, except that N, N, N'-trimethylethane-1,2-diamine was used in place of tert-butylmethyl (2- (methylamino) ethyl) carbamate (ii). To the intermediate product obtained 5-chloro-N- (2,4-dimethoxybenzyl) -4 - ((2- (dimethylamino) ethyl) (methyl) amino) -4-fluorophenyl) amino) -2-fluoro-N- (5 -fluoropyridine-2-yl) benzene sulfonamide (viii, 0.05 g, 0.08 mmol) 1 M HCl in ethyl acetate (5 mL) was added. After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 48.3%).

1H NMR (500 MHz, MeOD): 8.06 (d, 1H), 7.88 (d, 1H), 7.53 (m, 1H), 7.25 (dd, 1H), 7.16 (dd , 1H), 7.04 (m, 1H), 6.88 (m, 1H), 6.35 (d, 1H), 3.33 (t, 2H), 3.20 (t, 2H), 2 , 92 (s, 6H), 2.71 (s, 3H)

Example 138: Preparation of 5-chloro-4 - ((2 - ((2- (dimethylamino) ethyl) (methyl) amino) -4-fluorophenyl) amino) -2-fluoro-N- (thiazol-2-yl) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 137, except that thiazol-2-amine was used in place of 5-fluoropyridine-2-amine (iv). To the intermediate obtained 5-chloro-N - (2,4-dimethoxybenzyl) -4 - ((2- (dimethylamino) ethyl) (methyl) amino) -4-fluorophenyl) amino) -2-fluoro-N- (thiazole -2-yl) benzene sulfonamide (0.05 g, 0.08 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 48.4%).

1H NMR (500 MHz, MeOD): 7.83 (d, 1H), 7.27 (m, 1H), 7.12 (t, 1H), 7.04 (m, 1H), 6.90 (t , 1H), 6.75 (d, 1H), 6.40 (d, 1H), 3.34 (t, 2H), 3.22 (t, 2H), 2.83 (s, 6H), 2 , 73 (s, 3H)

Example 139: Preparation of 5-chloro-N- (5-chlorothiazol-2-yl) -4 - ((2 - ((2- (dimethylamino) ethyl) (methyl) amino) -4-fluorophenyl) amino) -2 -fluorobenzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 137, except that 5-chlorothiazol-2-amine was used in place of 5-fluoropyridine-2-amine (iv). To the intermediate obtained 5-c loro-N - (5-chlorothiazol-2-yl) -N- (2,4-dimethoxybenzyl) -4 - ((2 - ((2- (dimethylamino) ethyl) (methyl) amino ) -4-fluorophenyl) amino) -2-fluorobenzene sulfonamide (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 47.9%).

1H NMR (500 MHz, MeOD): 7.82 (d, 1H), 7.28 (t, 1H), 7.19 (d, 1H), 7.05 (d, 1H), 6.89 (t , 1H), 6.41 (d, 1H), 3.30 (t, 2H), 3.23 (t, 2H), 2.84 (s, 6H), 2.74 (s, 3H)

Example 140: Preparation of 5-chloro-N - (5-chlorothiazol-2-yl) -4 - ((2 - ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) amino) -2-fluorobenzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 137, except that 5-chlorothiazol-2-amine was used in place of 5-fluoropyridine-2-amine (iv) and 2-fluoro-1-nitrobenzene 2,4-Difluoro-1-nitrobenzene (i) was used in place. To the intermediate obtained 5-chloro-N - (5-chlorothiazol-2-yl) -N - (2,4-dimethoxybenzyl) -4 - ((2 - ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) amino) -2-fluorobenzene sulfonamide (0.05 g, 0.07 mmol) 1M HCl in ethyl acetate (5 mL) was added. After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 48.2%).

1H NMR (500 MHz, MeOD): 7.84 (d, 1H), 7.31 (t, 2H), 7.25 (t, 1H), 7.20 (t, 2H), 6.40 (d , 1H), 3.36 (t, 2H), 3.24 (t, 2H), 2.86 (s, 6H), 2.72 (s, 3H)

Example 141: Preparation of 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -N- (5-methylthiazol-2-yl ) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 103, except that 5-methylthiazol-2-amine was used in place of 5-fluoropyridine-2-amine (iv). To the intermediate obtained tert-butyl 2 - ((2 - ((2-chloro-4- (N- (2,4-dimethoxybenzyl) -N- (5-methylthiazol-2-yl) sulfamoyl) -5-fluorophenyl) amino) -5-fluorophenyl) (methyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.06 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 53.0%).

1H NMR (500 MHz, MeOD): 7.83 (d, 1H), 7.29 (dd, 1H), 7.05 (dd, 1H), 6.89 (t, 1H), 6.82 (s , 1H), 6.47 (d, 1H), 3.27 (t, 2H), 2.11 (t, 2H), 2.72 (s, 3H), 2.67 (s, 3H), 2 , 24 (s, 3H)

Example 142: Preparation of 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) -N- (oxazol-2-yl) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 133, except that oxazolo-2-amine was used in place of 5-methylisoxazolo-3-amine (iv). To the intermediate obtained tert-butyl (2 - ((2 - ((4 - (N - (tert-butoxycarbonyl) -N- (oxazol-2-yl) sulfamoyl) -2-chloro-5-fluorophenyl) amino) - 5-fluorophenyl) (methyl) amino) ethyl) (methyl) carbamate (0.03 g, 0.05 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.01g, 47.5%).

1H NMR (500 MHz, MeOD): 1H NMR (500 MHz, MeOD): 7.87 (d, 1H), 7.25-7.22 (m, 2H), 7.01 (d, 1H), 6 , 85-6.84 (m, 1H), 6.42 (d, 1H), 5.48 (s, 1H), 3.25-3.24 (m, 2H), 3.09-3.07 (m, 2H), 2.71 (s, 3H), 2.61 (s, 3H)

Example 143: Preparation of N- (5- (tert-butyl) isoxazol-3-yl) -5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamino) ethyl ) amino) phenyl) amino) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 133, except that 5— (tert-butyl) isoxazolo-3-amine was used in place of 5-methylisoxazolo-3-amine (iv). To the intermediate obtained tert-butyl (2 - ((2 - ((4- (N- (tert-butoxycarbonyl) -N- (5-tert-butyl) isoxazol-3-yl) sulfamoyl) -2-chloro-5 -fluorophenyl) amino) -5-fluorophenyl) (methyl) amino) ethyl) (methyl) carbamate (0.03 g, 0.04 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.01 g, 46.4%).

1H NMR (500 MHz, MeOD): 7.78 (d, 1H), 7.19-7.16 (m, 1H), 6.97 (d, 1H), 6.82-6.79 (m, 1H), 6.42 (d, 1H), 5.87 (s, 1H), 3.30-3.29 (m, 2H), 2.67 (s, 3H), 2.64 (s, 3H ), 1.23 (s, 9H)

Example 144: Preparation of N- (5- (tert-butyl) isoxazol-3-yl) -5-chloro-2-fluoro-4 - ((2- (methyl (2- (methylamino) ethyl) amino) phenyl ) amino) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 133, except that 5— (tertbutyl) isoxazolo-3-amine was used in place of 5-methylisoxazolo-3-amine (iv) and 1-fluoro-2 —Nitrobenzene was used in place of 2,4-difluoro-1-nitrobenzene (i). To the intermediate obtained tert-butyl (2 - ((2 - ((4— (N— (tert-butoxycarbonyl) —N— (5-tert-butyl) isoxazol-3-yl) sulfamoyl) —2-chloro — 5 —Fluorophenyl) amino) phenyl) (methyl) amino) ethyl) (methyl) carbamate (0.03 g, 0.04 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.01g, 46.0%).

1H NMR (500 MHz, MeOD): 7.83 (d, 1H), 7.23 (d, 2H), 7.14-7.10 (m, 2H), 6.70 (d, 1H), 5 , 89 (s, 1H), 3.30-3.27 (m, 2H), 3.13-3.11 (m, 2H), 2.66 (s, 6H), 1.23 (s, 9H )

Example 145: Preparation of 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (1,2,4-thiadiazole -5-yl) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 133, except that 1,2,4-thiadiazole-5-amine was used in place of 5-methylisoxazolo-3-amine (iv) and tert-butyl methyl (pyrrolidin-3-yl) carbamate was used in place of tert-butyl methyl (2- (methylamino) ethyl) carbamate (ii). To the intermediate obtained tert-butyl (1— (2 - ((4— (N— (tert-butoxycarbonyl) —N— (1,2,4-thiadiazol-5-yl) sulfamoyl) —2-chloro — 5— Fluorophenyl) amino) -5-fluorophenyl) pyrrolidin-3-yl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After shaking the mixture stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 56.0%).

1H NMR (500 MHz, MeOD): 8.39 (s, 1H), 7.80 (d, 1H), 7.14 (t, 1H), 6.73 (d, 1H), 6.68 (t , 1H), 6.08 (d, 1H), 3.78 (t, 1H), 3.58 (dd, 1H), 3.48 (m, 1H), 3.40 (dd, 1H), 2 , 67 (s, 3H), 2.34 (m, 1H), 1.99 (m, 1H)

Example 146: Preparation of 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (1-methyl-1H-pyrazole -3-yl) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 133, except that 1-methyl-1H-pyrazol-3-amine was used in place of 5-methylisoxazolo-3-amine (iv) and tert-butyl methyl (pyrrolidin-3-yl) carbamate was used in place of tert-butyl methyl (2- (methylamino) ethyl) carbamate (ii). To the intermediate obtained tert-butyl (1 - (2 - ((4- (N- (tert-butoxycarbonyl) -N- (1-methyl-1H-pyrazol-3-yl) sulfamoyl) -2-chloro-5- Fluorophenyl) amino) -5-fluorophenyl) pyrrolidin-3-yl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 56.1%).

1H NMR (500 MHz, MeOD): 7.68 (d, 1H), 7.38 (s, 1H), 7.13 (t, 1H), 6.75 (dd, 1H), 6.86 (t , 1H), 6.06 (d, 1H), 6.00 (s, 1H), 3.78 (t, 1H), 3.70 (s, 3H), 3.56 (dd, 1H), 3 , 48 (m, 1H), 3.41 (dd, 1H), 3.39 (s. 3H), 2.36 (m, 1H), 1.98 (m, 1H) Example 147: Preparation of 5- chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (pyrimidin-4-yl) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 133, except that pyrimidin-4-amine was used in place of 5-methylisoxazolo-3-amine (iv) and tert-butyl methyl (pyrrolidin-3-yl ) carbamate was used in place of tert-butyl methyl (2- (methylamino) ethyl) carbamate (ii). To the intermediate obtained tert-butyl ((4 - ((2- (3 - ((tertbutoxycarbonyl) (methyl) amino) pyrrolidin-1-yl) -4-fluorophenyl) amino) -5-chloro-2-fluorophenyl) sulfonyl ) (pyrimidin-4-yl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 56.2%).

1H NMR (500 MHz, MeOD): 8.45 (s, 1H), 8.44 (s, 1H), 7.95 (d, 1H), 7.12 (d, 1H), 7.00 (t , 1H), 6.72 (dd, 1H), 6.66 (td, 1H), 6.04 (d, 1H), 3.78 (t, 1H), 3.56 (dd, 1H), 3 , 47 (m, 1H), 3.40 (dd, 1H), 2.65 (s, 3H), 2.31 (m, 1H), 1.98 (m, 1H) Example 148: Preparation of 5- chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (5-fluoropyrimidin-2-yl) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 96, except that tert-butyl methyl (pyrrolidin-3-yl) carbamate was used in place of tert-butyl methyl (2- (methylamino) ethyl) carbamate ( ii). To the intermediate obtained tert-butyl (1- (2 - ((2-chloro-4- (N- (2,4-dimethoxybenzyl) -N- (5-fluoropyrim idin-2-yl) sulfamoyl) -5-fluorophenyl ) amino) -5-fluorophenyl) pyrrolidin-3-yl) (methyl) carbamate (0.05 g, 0.06 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 59.8%).

1H NMR (500 MHz, MeOD): 8.46 (s, 2H), 7.94 (d, 1H), 7.11 (td, 1H), 6.72 (d, 1H), 6.66 (td , 1H), 6.04 (d, 1H), 3.77 (t, 1H), 3.57 (dd, 1H), 3.48 (m, 1H), 3.41 (dd, 1H), 2 , 66 (s, 3H), 2.33 (m, 1H), 1.99 (m, 1H)

Example 149: Preparation of 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (pyrazin-2-yl) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 96, except that 2-chloropyrazine was used in place of 2-chloro-5-fluoropyrimidine (iv) and tert-butyl methyl (pyrrolidin-3-yl) carbamate Tert-butyl methyl (2- (methylamino) ethyl) carbamate (ii) was used in place. To the intermediate obtained tert-butyl (1- (2 - ((2-chloro-4- (N- (2,4-dimethoxyphenyl) -N- (pyrazin-2-yl) sulfamoyl) -5-fluorophenyl) amino) -5-fluorophenyl) pyrrolidin-3-yl) (methyl) carbamate (0.05 g, 0.06 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 60.9%).

1H NMR (500 MHz, MeOD): 8.29 (s, 1H), 8.15 (s, 1H), 8.09 (s, 1H), 7.88 (d, 1H), 7.09 (dd , 1H), 6.70 (dd, 1H), 6.64 (t, 1H), 6.05 (d, 1H), 5.45 (d, 1H), 3.76 (m, 1H), 3 , 54 (dd, 1H), 3.44 (m, 2H), 2.67 (s, 3H), 2.29 (m, 1H), 1.90 (m, 1H) Example 150: Preparation of 5- chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (5-methylisoxazol-3-yl) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 133, except that tert-butyl methyl (pyrrolidin-3-yl) carbamate was used in place of tert-butyl methyl (2- (methylamino) ethyl) carbamate (ii) . To the intermediate obtained tert-butyl (1- (2 - ((4- (N- (tert-butoxycarbonyl) -N- (5-methylisoxazol-3-yl) sulfamoyl) -2-chloro-5-fluorophenyl) amino) -5-fluorophenyl) pyrrolidin-3-yl) (methyl) carbamate (0.05 g, 0.06 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 56.1%).

1H NMR (500 MHz, MeOD): 7.80 (d, 1H), 7.14 (dd, 1H), 6.73 (d, 1H), 6.69 (dd, 1H), 6.09 (d , 1H), 6.07 (s, 1H), 3.76 (t, 1H), 3.58 (m, 2H), 3.43 (m, 2H), 2.66 (s, 3H), 2 , 32 (s, 3H), 2.05 (m, 2H)

Example 151: Preparation of 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (pyrimidin-5-yl) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 133, except that pyrimidin-5-amine was used in place of 5-methylisoxazol-3-amine (iv) and tert-butyl methyl (pyrrolidin-3-yl ) carbamate was used in place of tert-butyl methyl (pyrrolidin-3-yl) carbamate (ii). To the intermediate obtained tert-butyl (1- (2 - ((4- (N - (tertbutoxycarbonyl) (pyrimidin-5-yl) sulfamoyl) -2-chloro-5-fluorophenyl) amino) pyrrolidin-3-yl) ( methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, the Completion of the reaction was confirmed by TLC The reaction solution was filtered to obtain the target compound (0.02 g, 56.2%).

1H NMR (500 MHz, MeOD): 8.87 (s, 1H), 8.59 (d, 2H), 7.79 (d, 1h), 7.12 (td, 1H), 6.73 (d, 1H ), 6.67 (td, 1H), 6.07 (d, 1H), 3.76 (t, 1H), 3.50 (m, 2H), 3.54 (m, 2H), 2.67 (s, 3H), 2.32 (m, 1H), 1.98 (m, 1H)

Example 152: Preparation of 5-chloro-2-fluoro-4 - ((4-fluoro-2 - ((2- (methylamino) ethyl) amino) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 92, except that tert-butyl (2-aminoethyl) (methyl) carbamate was used in place of tert-butyl methyl (2- (methylamino) ethyl) carbamate ( ii). To the intermediate obtained tert-butyl (2 - ((2 - ((4 - (N- (tert-butoxycarbonyl) - N- (thiazole-4-yl) sulfamoyl) -2-chloro-5-fluorophenyl) amino) - 5-fluorophenyl) amino) ethyl) (methyl) carbamate (0.05 g, 0.07 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 56.9%).

1H NMR (500 MHz, MeOD): 8.72 (s, 1H), 7.75 (d, 1H), 7.07 (t, 1H), 7.00 (s, 1H), 6.63 (d , 1H), 6.49 (t, 1H), 6.05 (d, 1H), 3.46 (t, 2H), 3.17 (t, 2H), 2.70 (s, 3H)

Example 153: Preparation of 5-chloro-4 - ((2 - ((2- (dimethylamino) ethyl) amino) -4-fluorophenyl) amino) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 92, except that N, N-dimethylethane-1,2-diamine (3- (methylamino) propyl) carbamate was used in place of tert-butyl methyl (2 - (methylamino) ethyl) carbamate (ii). To the intermediate obtained tert-butyl (2 - ((4- (N- (tert-butoxycarbonyl) -N- (thiazol-4-yl) sulfamoyl) -2-chloro-5-fluorophenyl) amino) -5-fluorophenyl) (2- (dimethylamino) ethyl) carbamate (0.02 g, 0.0003 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.01g, 70.5%).

1H NMR (500 MHz, MeOD): 8.73 (s, 1H), 7.75 (d, 1H), 7.08 (t, 1H), 7.01 (s, 1H), 6.66 (d , 1H), 6.50 (t, 1H), 6.04 (d, 1H), 3.53 (t, 2H), 3.30 (t, 2H), 2.90 (s, 6H)

Example 154: Preparation of 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (3- (methylamino) propyl) amino) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide hydrochloride

An intermediate product was prepared in the same manner as described in Example 92, except that tert-butyl methyl (3- (methylamino) propyl) carbamate was used in place of tert-butyl methyl (2- (methylamino) ethyl) carbamate (ii). To the intermediate obtained tert-butyl (3 - ((2 - ((4- (N- (tert-butoxycarbonyl) -N- (thiazol-4-yl) sulfamoyl) -2-chloro-5-fluorophenyl) amino) - 5-fluorophenyl) (methyl) amino) propyl) (methyl) carbamate (0.05 g, 0.7 mmol) was added 1 M HCl in ethyl acetate (5 mL). After stirring the mixture was stirred overnight while warming to 50 to 60 ° C, completion of the reaction was confirmed by TLC. The reaction solution was filtered to obtain the target compound (0.02g, 55.9%).

1H NMR (500 MHz, MeOD): 8.74 (s, 1H), 7.78 (d, 1h), 7.25 (m, 1H), 7.03 (m, 2H), 6.88 (m , 1H), 6.29 (d, 1H), 3.06 (d, 2H), 2.80 (d, 2H), 2.70 (s, 3H), 2.60 (s, 3H), 1 , 81 (d, 2H).

Experimental Example

To measure the activities of the compounds of the invention as antagonists, a blocking effect experiment against sodium ion channel 1.7 (Nav1.7) and sodium ion channel 1.5 (Nav1.5) was carried out as follows. 1) Cell culture

The hNav 1.7 HEK 293 cell line was a cell line in which a human sodium ion channel 1.7 gene (type IX voltage-gated sodium channel alpha subunit) was stably expressed in human embryonic kidney (HEK) cells. 293 and was purchased from Millipore. The culture medium used was prepared by adding 1% 100X NEAA and 10 % heat inactivated f Bs to DMEM F-12, and then adding 1 % P / S to it as an antibiotic. G-418 was added as a restriction enzyme during subculture. The hNav1.7 HEK293 cells were grown to about 80% confluence in a 5% CO ² incubator at 37 ° C, in a T75 flask for 2 or 3 days, and detached from the flask by treatment with trypsin solution. 0.05%. The cells were then harvested by centrifugation and used in the experiment.

The hNav 1.5 HEK 293 cell line was a cell line in which a human sodium ion channel 1.5 gene (Homo sapiens sodium channel, voltage-gated, type V, alpha subunit (SCN 5 A)) was expressed in a stable in human embryonic kidney (HEK) 293 cells, and was purchased from Creacell. The culture medium used was prepared by mixing 2% 100X L-glutamine and 10% FBS heat inactivated with DMEM, and then adding 1% P / S to it as an antibiotic. G-418 was added as a restriction enzyme during subculture, and hNav1.5 HEK293 cells were grown to about 80% confluence in a 5% CO ² incubator at 37 ° C in a T75 flask for 2o. 3 days, and detached from the flask by treatment with 0.05% trypsin solution. The cells were then harvested by centrifugation and used in the experiment.

2) Preparation of compound samples

The compounds prepared in the Examples of the present invention were dissolved in dimethylsulfoxide (DMSO) and used in the experiment. 90 mM and 10 mM DMSO stock solutions were prepared from each of the compounds and diluted in an extracellular solution (4 mM KCl, 138 mM NaCl, 1 mM ^{MgCl 2} , 1.8 mM ^{CaCl 2} , 5.6 mM Glucose, 10 mM HEPES, pH 7.45) at various concentrations, so that the final DMSO concentration was 0.3% or less.

3) Measurement of sodium ion channel blocking effects

To measure the sodium ion channel blocking effect, a lonFlux16 automatic membrane fixation system (Fluxion, Inc.) and a dedicated plate were used. The cells were distributed in an extracellular solution (4 mM KCl, 138 mM NaCl, 1 mM ^{MgCl 2 , 1.8 mM CaCl 2} , 5.6 mM Glucose, 10 mM HEPES, pH 7.45), and then dispensed into the specified region of the plate, and each of the prepared compound samples were diluted to various concentrations and then dispensed into the specified region of the plate. After dispensing the cells, compound samples and an intracellular solution (100 mM CsF, 45 mM CsCI, 5 mM NaCl, 5 mM EGTA, 10 mM HEPES, pH 7.2) on the plate is complete, the plate is mounted on the system membrane binding, and it was measured whether the compounds inhibited the ion channel according to an established program.

Specifically, eight concentrations per compound were prepared and the percent inhibition was determined by calculating the percent inhibition of the maximum current, generated after treating the cells with each concentration of the compound for 50 seconds, relative to the maximum current. generated prior to compound treatment, and the IC ⁵⁰ value was calculated using the Sigma graphics program. The results of the calculation are shown in Tables 2 to 5 below.

[Table 2]

[Table 3]

[Table 4]

[Table 5]

Claims (1)

A compound represented by Chemical Formula 1 below, or a pharmaceutically acceptable salt thereof:

in Chemical Formula 1, R ¹ is hydrogen, C ^1-4 alkyl, C ^1-4 alkoxy, C ^1-4 haloalkyl, C ^1-4 haloalkoxy, halogen or cyano, R ² and R ³ are each independently hydrogen or halogen, R ⁴ is thiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl or thiadiazolyl, wherein R4 is unsubstituted or substituted with C1-4 alkyl or halogen, R ⁵ is -CH ² CH ² -N (R ⁷ ) (R8) or -CH ² CH ² CH ² -N (R ⁷ ) (R8), R6 is hydrogen or C ^1-4 alkyl; or R ⁵ and R6 together form C ^3-5 alkylene, (C ^2-4 alkylene) -N (R9) - (C2-4 alkylene) or (C ^2-4 alkylene) -O - (C ^2-4 alkylene) , wherein each of the C ^3-5 alkylene, or C ^2-4 alkylene is independently unsubstituted or substituted with one or two R ¹⁰ , R ⁷ , R8 and R ⁹ are each independently hydrogen, or C ^1-4 alkyl, R ¹⁰ is C ^1-4 alkyl, C ^1-4 alkoxy, halogen, amino, NH (C1-4 alkyl), N (C1-4 alkyl) ² , NHCO (C1-4 alkyl) or pyrrolidinyl, X ¹ is CR 'or N, where R' is hydrogen or halogen, X ² is CH or N, and X ³ is NR ", where R" is hydrogen or C ^1-4 alkyl. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by Chemical Formula 1 is represented by Chemical Formula 1 'below:

where, R ¹ is hydrogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, halogen or cyano, R ² and R ³ are each independently hydrogen or halogen, R ⁴ is thiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl or thiadiazolyl, wherein R4 is unsubstituted or substituted with C1-4 alkyl or halogen, R ¹¹ is hydrogen or C ^1-4 alkyl, R ¹² is hydrogen, C ^1-4 alkyl, C ^1-4 alkoxy, halogen, amino, NH (C1-4 alkyl), N (C1-4 alkyl) ² , NHCO (C1-4 alkyl) or pyrrolidinyl, X ¹ is CR 'or N, where R' is hydrogen or halogen, X ² is CH or N, and X ³ is NR ", where R" is hydrogen or C ^1-4 alkyl, X4 is a bond, NH, N (C1-4 alkyl) or O (oxygen), and n is an integer from 1 to 4. The compound or the pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R ¹ is hydrogen, methyl, methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine or cyano. 4. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R ² and R ³ are each independently hydrogen, fluorine or chlorine. 5. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R ⁵ and R6 together form C ^3-5 alkylene, (C ^2-4 alkylene) -N (R9) - (C2-4 alkylene ) or (C ^2-4 alkylene) -O- (C2-4 alkylene), and each of the C3-5 alkylene or C2-4 alkylene is independently unsubstituted or substituted with methyl, methoxy, fluoro, amino, NHCH ³ , N (CH3) 2, N (CH2CH3) 2, NHCOCH3 or pyrrolidinyl. 6. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R ⁵ , R6, and R ⁵ and R6 together with the nitrogen to which they are attached form any of those selected from the group consisting of the following :

7. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R ⁵ is -CH ² CH ² -NH -CH ³ , -CH ² CH ² CH ² -NH -CH ³ or -CH2CH2- N (CH3) 2, and R6 is hydrogen or methyl. 8. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein X ¹ is Ch, CF or N, X ² is CH or N, as long as both X ¹ and X ² are not N . 9. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein X ³ is NH. 10. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of: 1) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide, 2) 5-chloro-4 - ((4-chloro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide, 3) (R) -5-chloro-4 - ((4-chloro-2- (2-methylpiperazin-1-yl) phenyl) amino) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide , 4) (R) -5-chloro-4 - ((4-chloro-2- (3- (methylamine) piperidin-1-yl) phenyl) amino) -2-fluoro-N- (thiazol-4- yl) benzenesulfonamide, 5) (R) -N- (1- (5-chloro-2 - ((2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenyl) amino) phenyl) pyrrolidine- 3-yl) acetamide, 6) 5-chloro-4 - ((4-chloro-2- (3- (diethylamino) pyrrolidin-1-yl) phenyl) amino) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide, 7) 4 - ((2 - ([1,3-bipyrrolidin] -1-yl) -4-chlorophenyl) amino) -5-chloro-2-fluoro-N- (thiazol-4-yl) benzenesulfonamide, 8) 5-chloro-2-fluoro-4 - ((4-methyl-2- (3- (methylamine) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide, 9) (S) -5-chloro-4 - ((4-chloro-2- (3-m ethylpiperazin-1-yl) phenyl) amino) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide , 10) 4 - ((4-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide, 11) 3-chloro-4 - ((4-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide, 12) 3,5- Difluoro-4 - ((4-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide, 13) 2-fluoro-4 - ((4-fluoro-2- (3- (methylamino) pyrrolidin-1-yl) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide, 14) 4 - (( 2- (3- (methylamino) pyrrolidin-1-yl) -4- (trifluoromethoxy) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide, 15) 3,5-difluoro-4 - ((2- (3- (methylamino) pyrrolidin-1-yl) -4- (trifluoromethoxy) phenyl) amino) -N- (thiazol-4-yl) benzenesulfonamide, 16) 2-fluoro-4 - ((2- (3- (methyllamine) p¡rrol¡d¡n-1-¡l) -4- (tr¡fluoromethoxy) phenyl) amine) -N- (thiazol-4-yl) benzenesulfonamide, 17) 5-chloro-2-fluoro-4 - ((2- (3- (methylamno) p¡rrol¡d¡n-1-¡l) -4- (tr¡fluoromethox¡) fen¡ l) amino) -N- (thiazol-4-¡l) benzenesulfonamide, 18) 5-chloro-4 - ((5-chloro-3- (3- (meth¡lam¡no) p¡rrol¡d¡n-1-¡l) p¡r¡d¡n-2-¡ l) amine) -2-fluoro-N- (thiazol-4-l) benzenesulfonamide, 19) 5-chloro-4 - ((6-chloro-2- (3- (meth¡lam¡no) p¡rrol¡d¡n-1-¡l) p¡r¡d¡n-3-¡ l) amine) -2-fluoro-N- (thiazol-4-l) benzenesulfonamide, 20) 5-chloro-2-fluoro-4 - ((2- (3- (methylamno) p¡rrol¡d¡n-1-¡l) -4- (tr¡fluorometh¡l) fen ¡L) amine) -N- (thiazol-4-¡l) benzenesulfonamide, 21) 5-chloro-4 - ((4- (d¡fluoromethoxy¡) -2- (3- (meth¡lam¡no) p¡rrol¡d¡n-1-¡l) phen¡l) am¡ no) -2-fluoro-N- (thiazol-4-¡l) benzenesulfonamide, 22) (R) -4 - ((4-fluoro-2- (3- (methylamine) p¡per¡d¡n-1-¡l) phenl) am¡no) -N- (thiazol-4-¡l) benzenesulfonamide, 23) (R) -2-fluoro-4 - ((4-fluoro-2- (3- (methylamine) piper¡per¡ n-1-¡l) phen¡l) am¡no) -N- (th¡azol-4-¡l) benzenesulfonamide, 24) (R) -3-chloro-4 - ((4-fluoro-2- (3- (methylamno) p¡per¡d¡n-1-¡l) phen¡l) am¡no ) -N- (thiazol-4-¡l) benzenesulfonamide, 25) (R) -3,5-d¡fluoro-4 - ((4-fluoro-2- (3- (methylamno) p¡per¡d¡n-1-¡l) phen¡l ) amino) -N- (thiazol-4-¡l) benzenesulfonamide, 26) (R) -5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamno) p¡per¡d¡n-1-¡l) phen¡l ) amino) -N- (thiazol-4-¡l) benzenesulfonamide, 27) (R) -4 - ((4-fluoro-2- (3- (methylamine) p¡rrol¡d¡n-1-¡l) phenl) amine) -N- (thiazol-4-¡l) benzenesulfonamide, 28) (R) -2-fluoro-4 - ((4-fluoro-2- (3- (methylamine) p¡rrol¡d¡ n-1-¡l) phen¡l) am¡no) -N- (th¡azol-4-¡l) benzenesulfonamide, 29) (R) -3-chloro-4 - ((4-fluoro-2- (3- (methylamno) p¡rrol¡d¡n-1-¡l) phen¡l) am¡no ) -N- (thiazol-4-¡l) benzenesulfonamide, 30) (R) -3,5-d¡fluoro-4 - ((4-fluoro-2- (3- (methylamno) p¡rrol¡d¡n-1-¡l) phen¡l ) amino) -N- (thiazol-4-¡l) benzenesulfonamide, 31) (R) -5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamno) p¡rrol¡d¡n-1-¡l) phen¡l ) amino) -N- (thiazol-4-¡l) benzenesulfonamide, 32) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamno) p¡rrol¡d¡n-1-¡l) phen¡l) am¡no ) -N- (thiazol-4-¡l) benzenesulfonamide, 33) 4 - ((2- (3-am¡nopyrrol¡d¡n-1-¡l) -4-fluorophenyl) am¡no) -2-fluoro-N- (th¡azol-4 -¡L) benzenesulfonam¡da, 34) 4 - ((2- (3-am¡nopyrrol¡d¡n-1-¡l) -4-fluorophenyl) am¡no) -3-chloro- N- (thiazol-4-¡l) benzenesulfonam¡da, 35) 4 - ((2- (3-am¡nopyrrol¡d¡n-1-¡l) -4-fluorophen¡l) am ¡No) -5-chloro-2-fluoro-N- (thiazol-4-¡l) benzenesulfonamide, 36) 4 - ((2- (3- (methylamine) p¡rrol¡ d¡n-1-¡l) phen¡l) am¡no) -N- (th¡azol-4-¡l) benzenesulfonamide, 37) 2-fluoro-4 - ((2- (3- (methyllamine) p¡rrol¡d¡n-1-¡l) -4- (tr¡fluoromethyl) phen¡l) am No) -N- (thiazol-4-¡l) benzenesulfonamida, 38) 3-chloro-4 - ((2- (3- (methyllamine) p¡rrol¡d¡n-1-¡l) -4- (tr¡fluoromethyl) phen¡l) am No) -N- (thiazol-4-¡l) benzenesulfonamida, 39) 4 - ((4- (d¡fluoromethox¡) -2- (3- (meth¡lam¡no) p¡rrol¡d¡n-1-¡l) phen¡l) am¡no) -2 -fluoro-N- (thiazol-4-¡l) benzenesulfonamide, 40) 3-chloro-4 - ((4- (d¡fluoromethox¡) -2- (3- (meth¡lam¡no) p¡rrol¡d¡n-1-¡l) phen¡l) am¡ no) -N- (thiazol-4-¡l) benzenesulfonamide, 41) (R) -4 - ((4-fluoro-2- (3-fluoropyrrol¡d¡n-1-¡l) phen¡l) am¡no) -N- (th¡azol-4- L) benzenesulfonamide, 42) (R) -2-fluoro-4 - ((4-fluoro-2- (3-fluorop¡rrol¡d¡n-1-¡l) phen¡l) am¡no) -N- (t¡ azole-4-¡l) benzenesulfonam¡da, 43) (R) -3-chloro-4 - ((4-fluoro-2- (3-fluorop¡rrol¡d¡n-1-¡l) phen¡l ) amino) -N- (thiazol-4-¡l) benzenesulfonamida, 44) (R) -3,5-d¡fluoro-4 - ((4-fluoro-2- (3-fluorop ¡Rrol¡d¡n-1-¡l) phen¡l) am¡no) -N- (th¡azol-4-¡l) benzenesulfonam¡da, 45) (R) -5-chloro-2-fluoro -4 - ((4-fluoro-2- (3-fluoropyrrol¡d¡n-1-¡l) phen¡l) am¡no) -N- (th¡azol-4-¡l) benzenesulfonam¡ gives, 46) 2-fluoro-4 - ((3-fluoro-2- (3- (methylamine) p¡rrol¡d¡n-1-¡l) phenyl) amine) -N- (thiazol-4-¡l) benzenesulfonamide, 47) 3-chloro-4 - ((3-fluoro-2- (3- (methylamine) p¡rrol¡d¡n-1- ¡L) phen¡l) am¡no) -N- (th¡azol-4-¡l) benzenesulfonamida, 48) 5-chloro-2-fluoro-4 - ((3-fluoro-2- (3 - (meth¡lam¡no) p¡rrol¡d¡n-1-¡l) phen¡l) am¡no) -N- (th¡azol-4-¡l) benzenesulfonamide, 49) 2-fluoro-4 - ((2- (3- (methylamine) pırrol¡d¡n-1-¡l) phenyl) amine) -N- (thiazole -4-¡l) benzenesulfonamida, 50) 3-chloro-4 - ((2- (3- (methylamine) pırrol¡d¡n-1-¡l) phenl) amine) -N- (thiazole -4-¡l) benzenesulfonamida, 51) 3,5-d¡fluoro-4 - ((2- (3- (methylamine) p¡rrol¡d¡n-1-¡l) phenl) amino) -N- (thiazol-4-¡l) benzenesulfonamide, 52) 5-chloro-2-fluoro-4 - ((2- (3- (methylamine) p¡rrol¡d¡n-1- ¡L) phenl) amino) -N- (thiazol-4-¡l) benzenesulfonamide, 53) 2-fluoro-4 - ((4-methoxy-2- (3- (met ¡Lam¡no) p¡rrol¡d¡n-1-¡l) phen¡l) am¡no) -N- (th¡azol-4-¡l) benzenesulfonamide, 54) 3-chloro-4 - ((4-methox¡-2- (3- (meth¡lam¡no) p¡rrol¡d¡n-1 - ¡l) phen¡l) am¡no) -N- (th¡azol-4 -¡L) benzenesulfonam¡da, 55) 5-chloro-2-fluoro-4 - ((4-methox¡-2- (3- (methylam¡no) p¡rrol¡d¡n-1-¡ l) phenl) amino) -N- (thiazol-4-¡l) benzenesulfonamide, 56) (R) -4 - ((4-methoxy-2- (3- (methlamine) pnperdn-1-l) phenl) amine) -N - (thiazol-4-¡l) benzenesulfonamide, 57) (R) -2-fluoro-4 - ((4-methoxy-2- (3- (methylamine) piper¡ d¡n-1-¡l) phen¡l) am¡no) -N- (th¡azol-4-¡l) benzenesulfonamide, 58) (R) -3-chloro-4 - ((4-methoxy-2- (3- (methylamine) p¡per¡d¡n-1-¡l) phenyl) amine) -N- (thiazol-4-yl) benzenesulfonamide, 59) (R) -3,5-d¡fluoro-4 - ((4-methox¡-2- (3- (meth¡lam¡no) p¡per¡d¡n-1-¡l) phen¡ l) amino) -N- (thiazol-4-¡l) benzenesulfonamide, 60) (R) -5-chloro-2-fluoro-4 - ((4-methox¡-2- (3- (methylamine) p¡per¡d¡n-1-¡l) phen¡ l) amino) -N- (thiazol-4-¡l) benzenesulfonamide, 61) 3-chloro-4 - ((4-fluoro-2- (4-methylp¡peraz¡n-1-¡l) phen¡l) am¡no) -N- (th¡azol-4- ¡L) benzenesulfonam¡da, 62) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (4-methylp¡peraz¡n-1-¡l) phen¡l) am¡no ) -N- (thiazol-4-¡l) benzenesulfonamide, 63) (S) -5-chloro-4 - ((2- (3- (dimethylamine) p¡rrol¡ d¡n-1-¡l) -4-fluorophen¡l) am¡no) -2-fluoro-N- (th¡azol-4-¡l) benzenesulfonamide, 64) (S) -5-chloro-4 - ((2- (3- (d¡met¡lam¡no) p¡rrol¡d¡n-1-¡l) -4- (tr¡fluorometh¡l ) phenyl) amine) -2-fluoro-N- (thiazol-4-¡l) benzenesulfonamide, 65) 5-chloro-2-fluoro-4 - ((2- (4-methylp¡peraz¡n-1-¡l) -4- (tr¡fluorome¡l) phen¡l) am¡no) -N- (thiazol-4-¡l) benzenesulfonamide, 66) 5-chloro-4 - ((4- (d¡fluoromethox¡) -2- (4-methylp¡peraz¡n-1-¡l) phen¡l) am¡no) -2-fluoro- N- (thiazol-4-¡l) benzenesulfonamide, 67) 5-chloro-2-fluoro-4 - ((2- (4-methylp¡peraz¡n-1-¡l) -4- (tr¡fluoromethox¡) phen¡l) am¡no) - N- (thiazol-4-¡l) benzenesulfonamide, 68) (S) -3-chloro-4 - ((2- (3- (d¡met¡lam¡no) p¡rrol¡d¡n-1-¡l) -4- (tr¡fluorometh¡l ) phenyl) amino) -N- (thiazol-4-¡l) benzenesulfonamide, 69) (S) -2-fluoro-4 - ((4-fluoro-2- (3- (methylamno) p¡rrol¡d¡n-1-¡l) phen¡l) am¡no ) -N- (thiazol-4-¡l) benzenesulfonamide, 70) (S) -5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamine) p¡rrol¡d¡n-1-¡l) phen¡l ) amino) -N- (thiazol-4-¡l) benzenesulfonamide, 71) (S) -5-chloro-4 - ((2- (3- (d¡meth¡lam¡no) p¡rrol¡d¡n-1-¡l) -4-methoxyphen¡l) amino) -2-fluoro-N- (thiazol-4-¡l) benzenesulfonamida, 72) (S) -5-chloro-4 - ((4- (d¡fluoromethox¡) -2- (3- (d¡met¡lam¡no) p¡rrol¡d¡n-1-¡l) phenyl) amino) -2-fluoro-N- (thiazol-4-¡l) benzenesulfonamide, 73) (R) -5-chloro-4 - ((2- (3- (d¡meth¡lam¡no) p¡rrol¡d¡n-1-¡l) -4-fluorophenyl) am¡ no) -2-fluoro-N- (thiazol-4-¡l) benzenesulfonamide, 74) (R) -5-chloro-4 - ((2- (3- (d¡met¡lam¡no) p¡rrol¡d¡n-1-¡l) -4- (tr¡fluorometh¡l ) phenyl) amine) -2-fluoro-N- (thiazol-4-¡l) benzenesulfonamide, 75) (R) -5-chloro-4 - ((4- (d¡fluoromethox¡) -2- (3- (d¡met¡lam¡no) p¡rrol¡d¡n-1-¡l) phenyl) amino) -2-fluoro-N- (thiazol-4-¡l) benzenesulfonamide, 76) 4 - ((2- (1,4-d¡azepan-1-¡l) -4-fluorophenyl) am¡no) -5-chloro-2-fluoro-N- (th¡azol-4 -¡L) benzenesulfonam¡da, 77) 5-chloro-4 - ((4-kano-2- (3- (methylamine) p¡rrol¡d¡n-1-¡l) fen ¡L) amine) -2-fluoro-N- (thiazol-4-¡l) benzenesulfonamide, 78) (R) -N- (1- (2 - ((2-chloro-5-fluoro-4- (N- (thiazol-4-¡l) sulfamo¡l) phen¡l) am¡no ) -5- (tr¡fluorometh¡l) phen¡l) p¡rrol¡d¡n-3-¡l) acetamide, 79) (R) -N- (1- (2 - ((2-chloro-4- (N- (thiazol-4-¡l) sulfamo¡l) phenyl) amine) -5- (tr¡fluorometh¡l) phen¡l) p¡rrol¡d¡n-3-¡l) acetamide, 80) (S) -3-chloro-4 - ((2- (3- (methyllamine) p¡rrol¡d¡n-1-¡l) -4- (tr¡fluoromethyl) phen ¡L) amine) -N- (thiazol-4-¡l) benzenesulfonamide, 81) (S) -5-chloro-2-fluoro-4 - ((2- (3- (methylamine) p¡rrol¡d¡n-1-¡l) -4- (tr¡fluoromet ¡L) phenl) amino) -N- (thiazol-4-¡l) benzenesulfonamide, 82) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamno) acetyl) amino) - N- (thiazol-4-¡l) benzenesulfonamide, 83) 4 - ((2- (3-aminoacet¡d¡n-1-¡l) -4-fluorophenyl) am¡no) -5-chloro-2-fluoro-N- (th¡azole -4-¡l) benzenesulfonam¡da, 84) 5-chloro-4 - ((2- (3- (d¡meth¡lam¡no) acety¡d¡n-1-¡l) -4-fluorophen¡ l) amine) -2-fluoro-N- (thiazol-4-l) benzenesulfonamide, 85) N- (1- (2 - ((2-chloro-5-fluoro-4- (N- (thiazol-4-¡l) sulfamo¡l) phenyl) amine) -5- fluorophen¡l) acet¡d¡n-3-¡l) acetamide, 86) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3-methoxyp¡rrol¡d¡n-1-¡l) phen¡l) am¡no) -N- ( thiazol-4-¡l) benzenesulfonamida, 87) 5-chloro-2-fluoro-4 - ((2- (3-methoxyp¡rrol¡d¡n-1-¡l) -4- (tr¡fluoromethyl) phen¡l) am¡ no) -N- (thiazol-4-¡l) benzenesulfonamide, 88) (R) -N- (1- (2 - ((2-chloro-5-fluoro-4- (N- (thiazol-4-¡l) sulfamo¡l) phen¡l) am¡no ) -5-fluorophen¡l) p¡rrol¡d¡n-3-¡l) acetamide, 89) 3-chloro-4 - ((4-fluoro-2- (3-methox¡pyrrol¡d¡n-1-¡l) phen¡l) am¡no) -N- (th¡azol- 4-¡l) benzenesulfonam¡da, 90) 3-chloro-4 - ((2- (3-methoxy¡pyrrol¡d¡n-1-¡l) -4- (tr¡fluorometh¡l) fen ¡L) amine) -N- (thiazol-4-¡l) benzenesulfonamide, 91) (R) -N- (1- (2 - ((2-chloro-4- (N- ( th¡azol-4-¡l) sulfamo¡l) phen¡l) am¡no) -5-fluorophen¡l) p¡rrol¡d¡n-3-¡l) acetamide, 92) 5-chloro -2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamine) ethyl) amine) phenl) amine) -N- (t ¡Azole-4-¡l) benzenesulfonam¡da, 93) 3-chloro-4 - ((2 - ((2- (dimethylamine) ethyl) (methyl) amine) -4-fluorophenyl) amine) - N- (thiazol-4-¡l) benzenesulfonamide, 94) 5-chloro-4 - ((2 - ((2- (dimethylamine) ethyl) (methyl) amine) -4-fluorophenyl) amine) - 2-fluoro-N- (thiazol-4-yl) benzenesulfonamide, 95) 5-chloro-2-fluoro-4 - ((2- (methyl (2- (methylamine) ethyl) amine) -4- (trifluoromethyl) phen l) amino) -N- (thiazol-4-¡l) benzenesulfonamide, 96) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamine) ethyl) amine) phenyl) amine) -N- (5-fluorop¡r¡m¡d¡n-2-¡l) benzenesulfonam¡da, 97) 5-chloro-2-fluoro-N- (5-fluorop¡r¡m¡d¡n-2-¡l) -4 - ((2- (methyl (2- (meth¡lam¡no ) ethyl) amine) -4- (trifluoromethyl) phenl) amine) benzenesulfonamide, 98) 5-chloro-4 - ((4- (d¡fluoromethox¡) -2- (methyl (2- (methylamine) ethyl) amine) phenyl) amine ) -2-fluoro-N- (thiazol-4-¡l) benzenesulfonamide, 99) 5-chloro-4 - ((4-kano-2- (methyl (2- (methylamine) ethyl) amine) phenl) amine) -2 -fluoro-N- (thiazol-4-¡l) benzenesulfonamide, 100) 5-chloro-4 - ((4-kano-2- (methyl (2- (methylamine) ethyl) amine) phenl) amine) -2 -fluoro-N- (5-fluorop¡r¡m¡d¡n-2-¡l) benzenesulfonamida, 101) 5-chloro-4 - ((4- (d¡fluoromethox¡) -2- (methyl (2- (methylamine) ethyl) amine) phenyl) amine ) -2-fluoro-N- (5-fluorop¡r¡m¡d¡n-2-¡l) benzenesulfonamide, 102) 5-chloro-2-fluoro-N- (5-fluorop¡r¡m¡d¡n-2-¡l) -4 - ((2- (methyl (2- (meth¡lam¡no ) ethyl) amine) phenyl) amine) benzenesulfonamide, 103) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamine) ethyl) amine) phenyl) amine) -N- (5-fluorop¡r¡d¡n-2-¡l) benzenesulfonam¡da, 104) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamine) ethyl) amine) phenyl) amine) -N- (p¡r¡d¡n-2-¡l) benzenesulfonam¡da, 105) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamine) ethyl) amine) phenyl) amine) -N- (thiazol-2-¡l) benzenesulfonamide, 106) 5-chloro-4 - ((4-kano-2- (methyl (2- (methylamine) ethyl) amine) phenl) amine) -2 -fluoro-N- (5-fluorop¡r¡d¡n-2-¡l) benzenesulfonam¡da, 107) 5-chloro-4 - ((4-kano-2- (methyl (2- (methylamine) ethyl) amine) phenl) amine) -2 -fluoro-N- (p¡r¡d¡n-2-¡l) benzenesulfonamida, 108) 5-chloro-4 - ((4-kano-2- (methyl (2- (methylamine) ethyl) amine) phenl) amine) -2 -fluoro-N- (thiazol-2-¡l) benzenesulfonamide, 109) 5-chloro-2-fluoro-N- (5-fluorop¡r¡d¡n-2-¡l) -4 - ((2- (methyl (2- (methylamine) et ¡L) am¡no) -4- (tr¡fluorometal) phen¡l) am¡no) benzenesulfonamide, 110) 5-chloro-2-fluoro-4 - ((2- (methyl (2- (methylamine) ethyl) amine) -4- (trifluoromethyl) phen l) am¡no) -N- (p¡r¡d¡n-2-¡l) benzenesulfonam¡da, 111) 5-chloro-2-fluoro-4 - ((2- (methyl (2- (methylamine) ethyl) amine) -4- (trifluoromethyl) phen l) amino) -N- (thiazol-2-¡l) benzenesulfonamide, 112) 5-0! oro-2-fluoro-N- (5-fluorop¡ r¡d¡n-2-¡l) -4 - ((2- (methyl (2- (meth¡lam¡no) eth¡l ) amine) phenl) amine) benzenesulfonamide, 113) 5-chloro-2-fluoro-4 - ((2- (methyl (2- (methylamine) ethyl) amine) phenl) amine) -N- ( p¡r¡d¡n-2-¡l) benzenesulfonamida, 114) 5-chloro-2-fluoro-4 - ((2- (methyl (2- (methylamine) ethyl) amine) phenl) amine) -N- ( thiazol-2-¡l) benzenesulfonamida, 115) 5-chloro-4 - ((4- (d¡fluoromethoxy) -2- (methyl (2- (methylamine) et¡ l) amine) phenl) amine) -2-fluoro-N- (5-fluoropyr¡d¡n-2-l) benzenesulfonamide, 116) 5-chloro-4 - ((4- (d¡fluoromethoxy) -2- (methyl (2- (methylamine) ethyl) amine) phenl) amine ) -2-fluoro-N- (thiazol-2-¡l) benzenesulfonamide, 117) 5-chloro-4 - ((4- (d¡fluoromethoxy) -2- (methyl (2- (methlamine) ethyl) amine) phenl) amine ) -2-fluoro-N- (p¡r¡d¡n-2-¡l) benzenesulfonam¡da, 118) 5-chloro-2-fluoro-N- (5-fluorop¡r¡d¡n-2-¡l) -4 - ((4-methox¡-2- (methyl (2- (met¡ lam¡no) eth¡l) am¡no) phen¡l) am¡no) benzenesulfonamide, 119) 5-chloro-2-fluoro-4 - ((4-methoxy-2- (methyl (2- (methylamine) ethyl) amine) phenyl) amine ) -N- (thiazol-2-¡l) benzenesulfonamide, 120) 5-chloro-2-fluoro-4 - ((4-methoxy-2- (methyl (2- (methylamine) ethyl) amine) phenyl) amine ) -N- (thiazol-4-¡l) benzenesulfonamide, 121) 5-chloro-2-fluoro-4 - ((2- (methyl (2- (methylamine) ethyl) amine) phenl) amine) -N- ( thiazol-4-¡l) benzenesulfonamide, 122) 5-chloro-2-fluoro-N- (5-fluorop¡r¡m¡d¡n-2-¡l) -4 - ((4- methoxy-2- (methyl (2- (methylamine) ethyl) amine) phenyl) amine) benzenesulfonamide, 123) 5-chloro-4 - ((4-chloro-2- (methyl (2- (methlamine) ethyl) amine) phenl) amine) -2-fluoro -N- (thiazol-4-¡l) benzenesulfonamide, 124) 5-chloro-4 - ((4-chloro-2- (methyl (2- (methylamine) ethyl) amine) phenl) amine) -2-fluoro -N- (5-fluorop¡r¡m¡d¡n-2-¡l) benzenesulfonam¡da, 125) 5-chloro-4 - ((4-chloro-2- (methyl (2- (methylamine) ethyl) amine) phenl) amine) -2-fluoro -N- (5-fluorop¡r¡d¡n-2-¡l) benzenesulfonam¡da, 126) 5-chloro-4 - ((4-chloro-2- (methyl (2- (methylamine) ethyl) amine) phenl) amine) -2-fluoro -N- (thiazol-2-¡l) benzenesulfonamide, 127) 5-chloro-N- (5-chlorotazol-2-¡l) -2-fluoro-4 - ((4-fluoro-2- (m eth¡l (2- (methylamine) ethyl) amine) phenl) amine) benzenesulfonamide, 128) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamine) ethyl) amino) phenyl) amino) -N - (5-Fluorothazol-2-yl) benzenesulfonamide, 129) 5-chloro-N- (5-chlorotazol-2-¡l) -2-fluoro-4 - ((2- (m-ethyl (2- (methylamine) ethyl) amine) phenl) amine) benzenesulfonamide, 130) 5-chloro-N- (5-chlorotazol-2-¡l) -2-fluoro-4 - ((4-methoxy-2- (methyl (2- (methylamine) ethyl) amine) phenl) amine) benzenesulfonamide, 131) 5-chloro-2-fluoro-N- (5-fluorotazole-2-¡l) -4 - ((2- (methyl (2- (methylamine) ethyl) am No) phenl) amine) benzenesulfonamide, 132) 5-chloro-2-fluoro-N- (5-fluorotazole-2-¡l) -4 - ((4-methoxy-2- (methyl (2- (methylamine) ethyl) amine) phenl) amine) benzenesulfonamide, 133) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamine) ethyl) amine) phenyl) amine) -N- (5-meth¡l¡soxazol-3-¡l) benzenesulfonamida, 134) 5-chloro-2-fluoro-4 - ((2- (methyl (2- (methylamine) ethyl) amine) phenl) amine) -N- ( 5-meth¡l¡soxazol-3-¡l) benzenesulfonam¡da, 135) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamine) ethyl) amine) phenyl) amine) -N- (5-methyl-1H-prazol-3-¡l) benzenesulfonamide, 136) 5-chloro-2-fluoro-4 - ((2- (methyl (2- (methylamine) ethyl) amine) phenyl) amine) -N- ( 5-methyl-1H-prazol-3-¡l) benzenesulfonamide, 137) 5-chloro-4 - ((2 - ((2- (dimethylamine) ethyl) (methyl) amine) -4-fluorophenyl) amine) - 2-fluoro-N- (5-fluorop¡r¡d¡n-2-¡l) benzenesulfonam¡da, 138) 5-chloro-4 - ((2 - ((2- (dimethyl) ethyl) (methyl) amine) -4-fluorophenyl) amine) - 2-fluoro-N- (thiazol-2-¡l) benzenesulfonamide, 139) 5-chloro-N- (5-chlorot¡azol-2-¡l) -4 - ((2 - ((2- (dimet¡lam¡no) eth¡l) (methyl) am No) -4-fluorophene (l) amine) -2-fluorobenzenesulfonamide, 140) 5-chloro-N- (5-chlorot¡azol-2-¡l) -4 - ((2 - ((2- (dimet¡lam¡no) eth¡l) (methyl) am No) phenl) amine) -2-fluorobenzenesulfonamide, 141) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamine) ethyl) amine) phenyl) amine) -N- (5-methyllazol-2-¡l) benzenesulfonamide, 142) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (methylamine) ethyl) amine) phenyl) amine) -N- (oxazol-2-¡l) benzenesulfonamide, 143) N- (5- (tert-butyl) ¡soxazol-3-¡l) -5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (2- (met ¡Lam¡no) eth¡l) am¡no) phen¡l) am¡no) benzenesulfonamide, 144) N- (5- (tert-butyl) ¡soxazol-3-¡l) -5-chloro-2-fluoro-4 - ((2- (methyl (2- (methylamine ) ethyl) amine) phenyl) amine) benzenesulfonamide, 145) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamno) p¡rrol¡d¡n-1-¡l) phen¡l) am¡no ) -N- (1,2,4-thiazol-5-¡l) benzenesulfonamide, 146) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamno) p¡rrol¡d¡n-1-¡l) phenl) am¡no ) -N- (1-methyl-1H-pyrazol-3-¡l) benzenesulfonamide, 147) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamno) p¡rrol¡d¡n-1-¡l) phen¡l) am¡no ) -N- (p¡r¡m¡d¡n-4-¡l) benzenesulfonam¡da, 148) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamno) p¡rrol¡d¡n-1-¡l) phen¡l) am¡no ) -N- (5-fluorop¡r¡m¡d¡n-2-¡l) benzenesulfonam¡da, 149) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamno) p¡rrol¡d¡n-1-¡l) phen¡l) am¡no ) -N- (p¡raz¡n-2-¡l) benzenesulfonam¡da, 150) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamno) p¡rrol¡d¡n-1-¡l) phen¡l) am¡no ) -N- (5-meth¡l¡soxazol-3-¡l) benzenesulfonamida, 151) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (3- (methylamno) p¡rrol¡d¡n-1-¡l) phenl) am¡no ) -N- (p¡r¡m¡d¡n-5-¡l) benzenesulfonam¡da, 152) 5-chloro-2-fluoro-4 - ((4-fluoro-2 - ((2- (methylamine) ethyl) amine) phenyl) amine) -N- (thiazol-4-¡l) benzenesulfonamide, 153) 5-chloro-4 - ((2 - ((2- (dimethylamine) ethyl) amine) -4-fluorophenyl) amine) -2-fluoro-N - (thiazol-4-¡l) benzenesulfonamide, and 154) 5-chloro-2-fluoro-4 - ((4-fluoro-2- (methyl (3- (methylamine) propyl) amine) phenyl) amine) -N- (thiazol-4-l) benzenesulfonamide. A pharmaceutical composition for use in a method of preventing or treating diseases related to sodium channel blockers comprising the compound or a pharmaceutically acceptable salt thereof According to any one of the revisions 1 to 10 as an active ingredient, where the diseases related to sodium channel blockers are acute pain, chronic pain, neuropathic pain, postoperative pain, pain, pain, arthralgia, neuropathy, nerve damage, diabetic neuropathy, neuropathic disease, epilepsy, arr ¡Tm¡a, m¡otonia, atax¡a, multiple scleros, unstable intrest syndrome, urinary continuation, visceral pain, depression on, eritralgia or PEPD (paroxysmal extreme pain disorder).